Bicyclic Anilide Spirolactam Cgrp Receptor Antagonists

ABSTRACT

The present invention is directed to compounds of Formula (I): (where variables A 1 , A 2 , B, J, K, m, n, R 4 , R 5a , R 5b  and R 5c  are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate, processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively. CGRP-alpha and CGRP-beta display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase. CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.

Based on pharmacological properties, these receptors are divided into at least two subtypes, denoted CGRP₁ and CGRP₂. Human □-CGRP-(8-37), a fragment of CGRP that lacks seven N-terminal amino acid residues, is a selective antagonist of CGRP₁, whereas the linear analogue of CGRP, diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selective agonist of CGRP₂. CGRP is a potent vasodilator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache. In clinical studies, elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to be the major source of headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle meningeal artery, the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP. Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al., Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531). Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol., 2000, 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distention of dural blood vessels during migraine headache may sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extra-cranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). A CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans. Such disorders include migraine and cluster headache (Doods, Curr Opin Inves Drugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14, 320-327); chronic tension type headache (Ashina et al., Neurology, 2000, 14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282); chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenic inflammation and inflammatory pain (Holzer, Neurosci., 1988, 24, 739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538; Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May et al. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int. Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus (Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders; inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchial hyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30 (8), 1794-1798); opiate withdrawal syndrome (Salmon et al., Nature Neurosci., 2001, 4(4), 357-358) morphine tolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, Fla.), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al., J. Membrane Biology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology, 2002, 37(4) 414-422) and cystitis. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache. Compelling evidence of the efficacy of CGRP antagonists for the treatment of migraine has been provided by clinical studies using intravenously administered BIBN4096BS. This CGRP antagonist was found to be a safe and effective acute treatment for migraine (Olesen et al., N. Engl. J. Med., 2004, 350(11), 1104-1110).

The present invention relates to compounds that are useful as ligands for CGRP receptors, in particular antagonists for CGRP receptors, processes for their preparation, their use in therapy, pharmaceutical compositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein: B is a bicycloheterocycle selected from the group consisting of:

-   -   where T, U, V, W, X and Y are each independently a carbon atom         or a nitrogen atom, wherein no more than two of T, U, V and W,         and no more than three of T, U, V, W, X and Y, are a nitrogen         atoms,         B is unsubstituted or substituted with 1-5 substituents each         independently selected from R¹, R², R^(3a) and R^(3b), wherein         R¹, R², R^(3a) and R^(3b) are independently selected from:     -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7         substituents each independently selected from:         -   (a) halo,         -   (b) hydroxy,         -   (c) —O—C₁₋₆alkyl,         -   (d) —C₃₋₆cycloalkyl,         -   (e) phenyl or heterocycle, wherein heterocycle is selected             from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,             piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl,             thienyl and morpholinyl, which phenyl or heterocycle is             unsubstituted or substituted with 1-5 substituents each             independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo,             hydroxy, trifluoromethyl and —OCF₃,         -   (f) —CO₂R⁹, wherein R⁹ is independently selected from:             hydrogen, —C₁₋₆alkyl which is unsubstituted or substituted             with 1-6 fluoro, —C₃₋₆cycloalkyl, benzyl and phenyl,         -   (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently             selected from:             -   hydrogen, —C₁₋₆alkyl which is unsubstituted or                 substituted with 1-6 fluoro, —C₅₋₆cycloalkyl, benzyl,                 phenyl, —COR⁹ and —SO₂R¹²,         -   (h) —SO₂R¹², wherein R¹² is independently selected from:             —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6             fluoro, —C₅₋₆cycloalkyl, benzyl and phenyl,         -   (i) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each             independently selected from:             -   hydrogen, —C₁₋₆alkyl which is unsubstituted or                 substituted with 1-6 fluoro, —C₅₋₆cycloalkyl, benzyl and                 phenyl,             -   or R^(10a) and R^(11a) are joined to form a ring                 selected from azetidinyl, pyrrolidinyl, piperidinyl,                 piperazinyl and morpholinyl, which ring is unsubstituted                 or substituted with 1-5 substituents each independently                 selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxyl,                 phenyl and benzyl,         -   (j) trifluoromethyl,         -   (k) —OCO₂R⁹,         -   (l) —(NR^(10a))CO₂R⁹,         -   (m) —O(CO)NR^(10a)R^(11a),         -   (n) —(NR⁹)(CO)NR^(10a)R^(11a), and         -   (o) —O—C₃₋₆cycloalkyl,     -   (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with         1-7 substituents each independently selected from:         -   (a) halo,         -   (b) hydroxy,         -   (c) —O—C₁₋₆alkyl,         -   (d) trifluoromethyl,         -   (e) phenyl, which is unsubstituted or substituted with 1-5             substituents each independently selected from: —C₁₋₆alkyl,             —O—C₁₋₆alkyl, halo, hydroxy and trifluoromethyl,     -   (3) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,         pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl,         isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl,         benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,         benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl,         indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,         isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl,         2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl,         pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl, purinyl,         naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl,         piperidinyl, tetrahydropyranyl, tetrahydrothienyl,         tetrahydrothiopyranyl, and morpholinyl, which phenyl or         heterocycle is unsubstituted or substituted with 1-5         substituents each independently selected from:         -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with             1-6 fluoro,         -   (b) halo,         -   (c) hydroxy,         -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with             1-6 fluoro,         -   (e) —C₃₋₆cycloalkyl,         -   (f) phenyl or heterocycle, wherein heterocycle is selected             from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, or             morpholinyl,             -   which is unsubstituted or substituted with 1-5                 substituents where the substituents are independently                 selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy                 and trifluoromethyl,         -   (g) —CO₂R⁹,         -   (h) —(CO)R⁹,         -   (i) —NR¹⁰R¹¹,         -   (j) —CONR¹⁰R¹¹,         -   (k) oxo         -   (l) —SR¹²,         -   (m) —S(O)R¹², and         -   (n) —SO₂R¹²,     -   (4) halo,     -   (5) oxo,     -   (6) hydroxy,     -   (7) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5         halo,     -   (8) —CN,     -   (9) —CO₂R⁹,     -   (10) —NR¹⁰R¹¹,     -   (11) —SO₂R¹²,     -   (12) —CONR^(10a)R^(11a),     -   (13) —OCO₂R⁹,     -   (14) —(NR^(10a))CO₂R⁹,     -   (15) —O(CO)NR^(10a)R^(11a),     -   (16) —(NR⁹)(CO)NR^(10a)R^(11a),     -   (17) —(CO)—(CO)NR^(10a)R^(11a),     -   (18) —(CO)—(CO)OR⁹, and     -   (19) —SO₂NR^(10a)R^(11a);     -   or R^(3a) and R^(3b) and the carbon atom(s) to which they are         attached are joined to form a ring selected from cyclobutyl,         cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,         azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,         tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl,         thienyl, dihydrothienyl, tetrahydrothienyl, dihydrothiopyranyl,         tetrahydrothiopyranyl and piperazinyl, which ring is         unsubstituted or substituted with 1-5 substituents each         independently selected from:         -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with             1-3 substituents each independently selected from:             -   (i) halo,             -   (ii) hydroxy,             -   (iii) —O—C₁₋₆alkyl,             -   (iv) —C₃₋₆cycloalkyl,         -   (v) phenyl or heterocycle, wherein heterocycle is selected             from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,             piperidinyl, piperazinyl, pyrrolidinyl, thienyl and             morpholinyl, which phenyl or heterocycle is unsubstituted or             substituted with 1-5 substituents each independently             selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy,             trifluoromethyl and —OCF₃,             -   (vi) —CO₂R⁹,             -   (vii) —NR¹⁰R¹¹,             -   (viii) —SO₂R¹²,             -   (ix) —CONR^(10a)R^(11a), and             -   (x) —(NR^(10a))CO₂R⁹,         -   (b) phenyl or heterocycle, wherein heterocycle is selected             from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,             pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which             phenyl or heterocycle is unsubstituted or substituted with             1-3 substituents each independently selected from:             —C₁₋₆alkyl which is unsubstituted or substituted with 1-6             fluoro, halo, hydroxy, —O—C₁₋₆alkyl, which is unsubstituted             or substituted with 1-6 fluoro, and —C₃₋₆cycloalkyl,         -   (c) halo,         -   (d) —SO₂R¹²,         -   (e) hydroxy,         -   (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with             1-5 halo,         -   (g) —CN,         -   (h) —COR¹²,         -   (i) —NR¹⁰R¹¹,         -   (j)—CONR^(10a)R^(11a),         -   (k) —CO₂R⁹,         -   (l) —(NR^(10a))CO₂R⁹,         -   (m) —O(CO)NR^(10a)R^(11a),         -   (n) —(NR⁹)(CO)NR^(10a)R^(11a), and         -   (o) oxo;             A¹ and A² are each independently selected from: a bond and             —CR¹³R¹⁴—,     -   wherein R¹³ and R¹⁴ are each independently selected from:         hydrogen, C₁₋₆ alkyl which is unsubstituted or substituted with         1-6 fluoro, hydroxy and halo,         wherein one of A¹ and A² is optionally absent;         J is independently selected from: ═C(R^(6a))—, —CR¹³R¹⁴— and         —C(═O)—;         K is independently selected from: ═C(R^(6b))—, —CR¹³R¹⁴—,         —C(═O)—, —SO₂—, ═N— and —N(R^(6b))—;         R⁴ is independently selected from: hydrogen, C₁₋₆ alkyl which is         unsubstituted or substituted with 1-6 fluoro, C₅₋₆ cycloalkyl,         benzyl and phenyl;         R^(5a), R^(5b) and R^(5c) are each independently selected from:         hydrogen, C₁₋₆ alkyl, —O—C₁₋₆alkyl, —OCF₃, trifluoromethyl,         halo, hydroxy and —CN;         R^(6a) and R^(6b) are each independently selected from:     -   (1) hydrogen;     -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5         substituents each independently selected from:         -   (a) halo,         -   (b) —O—C₁₋₆alkyl,         -   (c) —C₃₋₆cycloalkyl,         -   (d) phenyl or heterocycle, wherein heterocycle is selected             from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl,             pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,             thiazolyl, thienyl, triazolyl and morpholinyl, which phenyl             or heterocycle is unsubstituted or substituted with 1-3 each             independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo,             hydroxy, trifluoromethyl and —OCF₃,     -   (3) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl,         azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,         tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or         heterocycle is unsubstituted or substituted with 1-3         substituents each independently selected from: —C₁₋₄alkyl which         is unsubstituted or substituted with 1-5 fluoro, —O—C₁₋₄alkyl,         which is unsubstituted or substituted with 1-5 fluoro, halo,         hydroxy, —C₃₋₆cycloalkyl and phenyl,     -   (4) halo,     -   (5) hydroxy,     -   (6) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5         halo,     -   (7) —CN,     -   (8) —CO₂R⁹,     -   (9) —NR¹⁰R¹¹, and     -   (10) —CONR^(10a)R^(11a);         or R^(6a) and R^(6b) and the atom(s) to which they are attached         are joined to form a ring selected from cyclopentenyl,         cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl,         pyridazinyl, furanyl, dihydrofuranyl, dihydropyranyl, thiazolyl,         isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl,         thienyl, dihydrothienyl and dihydrothiopyranyl, which ring is         unsubstituted or substituted with 1-5 substituents each         independently selected from:     -   (a) —C₁₋₆alkyl which is unsubstituted or substituted with 1-3         substituents each independently selected from:         -   (i) halo,         -   (ii) hydroxy,         -   (iii) —O—C₁₋₆alkyl,         -   (iv) —C₃₋₆cycloalkyl,         -   (v) phenyl or heterocycle, wherein heterocycle is selected             from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,             piperidinyl, piperazinyl, pyrrolidinyl, thienyl and             morpholinyl, which phenyl or heterocycle is unsubstituted or             substituted with 1-5 substituents each independently             selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy,             trifluoromethyl and —OCF₃,         -   (vi) —CO₂R⁹,         -   (vii) —NR¹⁰R¹¹,         -   (viii) —SO₂R¹²,         -   (ix) —CONR^(10a)R^(11a) and         -   (x) —(NR^(10a))CO₂R⁹,     -   (b) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,         pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which         phenyl or heterocycle is unsubstituted or substituted with 1-3         substituents each independently selected from: —C₁₋₆alkyl which         is unsubstituted or substituted with 1-6 fluoro, —O—C₁₋₆alkyl         which is unsubstituted or substituted with 1-6 fluoro, halo,         hydroxyl and —C₃₋₆cycloalkyl,     -   (c) halo,     -   (d) —SO₂R¹²,     -   (e) hydroxy,     -   (f) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5         halo,     -   (g) —CN,     -   (h) —COR¹²,     -   (i) —NR¹⁰R¹¹,     -   (i) —CONR^(10a)R^(11a),     -   (k) —CO₂R⁹,     -   (l) —(NR^(10a))CO₂R⁹,     -   (m) —O(CO)NR^(10a)R^(11a),     -   (n) —(NR⁹)(CO)NR^(10a)R^(11a), and     -   (o) oxo;         m is 1 or 2;         n is 1 or 2;         and pharmaceutically acceptable salts thereof and individual         enantiomers and diastereomers thereof.

An embodiment of the present invention includes compounds of the formula Ia:

wherein A¹, A², B, J, K, R⁴, m, and n are defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of the formula Ib:

wherein B, J, K, R⁴, m, and n are defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of the formula Ic:

wherein B, J, and K are defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of the formula Id:

wherein B, J, and K are defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of the formula Ie:

wherein B is defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of the formula If:

wherein B is defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of the formula Ig:

wherein B is defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

In an embodiment of the present invention B is selected from the group consisting of:

which is unsubstituted or substituted with 1-5 substituents selected from R¹, R², R^(3a) and R^(3b), wherein R¹, R², R^(3a) and R^(3b) are defined herein.

In an embodiment of the present invention B is 2-oxobenzimidazolinyl.

In an embodiment of the present invention B is indolyl.

In an embodiment of the present invention B is indolinyl.

In an embodiment of the present invention B is 2-oxoindolinyl.

In an embodiment of the present invention B is 2-oxoazabenzimidazolinyl.

In an embodiment of the present invention B is azaindolyl.

In an embodiment of the present invention R¹, R², R^(3a) and R^(3b) are independently selected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5         substituents each independently selected from:         -   (a) fluoro,         -   (b) phenyl or heterocycle, wherein heterocycle is selected             from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,             piperidinyl, piperazinyl, pyrrolidinyl, thienyl and             morpholinyl,         -   (c) —CO₂R⁹, wherein R⁹ is independently selected from:             hydrogen, and —C₁₋₆alkyl,         -   (d) —CONR^(10a)R^(11a), wherein R^(10a) and R¹¹a are each             independently selected from: hydrogen and —C₁₋₆alkyl,             -   or R^(10a) and R^(11a) are joined to form a ring                 selected from azetidinyl, pyrrolidinyl, piperidinyl,                 piperazinyl and morpholinyl, and         -   (e) —O—C₃₋₆cycloalkyl,     -   (2) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,         pyrrolidinyl, thiazolyl, isothiazolyl, 2-oxopyrrolidinyl,         tetrahydrofuryl, piperidinyl, tetrahydrothienyl and         tetrahydrothiopyranyl, which phenyl or heterocycle is         unsubstituted or substituted with 1-5 substituents each         independently selected from:         -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with             1-3 fluoro,         -   (b) halo,         -   (c) —CO₂R⁹, wherein R⁹ is selected from: hydrogen,             —C₁₋₄alkyl, and —C₃₋₆cycloalkyl,         -   (d) —(CO)R⁹,         -   (e) CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are             independently selected from: hydrogen and —C₁₋₆alkyl,             -   or R^(10a) and R^(11a) are joined to form a ring                 selected from azetidinyl, pyrrolidinyl, piperidinyl,                 piperazinyl, and morpholinyl,         -   (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with             1-3 fluoro,         -   (g) hydroxy,         -   (h) oxo,         -   (i) —S—C₁₋₄alkyl,         -   (j) —S(O)—C₁₋₄alkyl, and         -   (k) —SO₂—C₁₋₄alkyl,     -   (3) halo,     -   (4) hydroxy,     -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3         fluoro,     -   (6) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently         selected from: hydrogen, —C₁₋₄alkyl which is unsubstituted or         substituted with 1-5 fluoro, —C₅₋₆cycloalkyl, and —COR⁹, wherein         R⁹ is defined herein.     -   (7) —C₃₋₆cycloalkyl,     -   (8) —(CO)—(CO)NR^(10a)R^(11a), wherein R^(10a) and R^(11a) are         independently selected from:         -   hydrogen and —C₁₋₆alkyl, and     -   (9) —CN.

In an embodiment of the present invention R¹ and R² are independently selected from:

-   -   (1) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5         substituents each independently selected from:         -   (a) fluoro,         -   (b) phenyl,         -   (c) —CO₂R⁹, wherein R⁹ is independently selected from:             hydrogen and —C₁₋₁₄alkyl,         -   (d) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each             independently selected from:             -   hydrogen and —C₁₋₁₄alkyl,             -   or R^(10a) and R^(11a) are joined to form a ring                 selected from azetidinyl, pyrrolidinyl, piperidinyl,                 piperazinyl, and morpholinyl, and         -   (e) —O—C₃₋₆cycloalkyl,     -   (2) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl,         thiazolyl, tetrahydrofuryl, piperidinyl and         tetrahydrothiopyranyl, which phenyl or heterocycle is         unsubstituted or substituted with 1-5 substituents each         independently selected from:         -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with             1-3 fluoro         -   (b) halo,         -   (c) —CO₂R⁹, wherein R⁹ is selected from: hydrogen,             —C₁₋₄allyl, and —C₃₋₆cycloalkyl,         -   (d) —(CO)R⁹,         -   (e) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are             independently selected from:             -   hydrogen and —C₁₋₄allyl,         -   (f) —O—C₁₋₄alkyl, which is unsubstituted or substituted with             1-3 fluoro,         -   (g) hydroxy,         -   (h) oxo         -   (i) —S—C₁₋₄allyl,         -   (j) —S(O)—C₁₋₄allyl, and         -   (k) —SO₂—C₁₋₄allyl,     -   (3) halo,     -   (4) hydroxy,     -   (5) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3         fluoro,     -   (6) —CN,     -   (7) —C₃₋₆cycloalkyl,     -   (8) —(CO)—(CO)NR^(10a)R^(11a), wherein R^(10a) and R^(11a) are         independently selected from:         -   hydrogen and —C₁₋₄alkyl, and     -   (9) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently         selected from: hydrogen, —C₁₋₄alkyl, and —COR⁹, wherein R⁹ is         defined herein.

In an embodiment of the present invention, R^(3a) and R^(3b) and the carbon atom(s) to which they are attached are joined together to form a ring selected from piperidinyl, cyclohexyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, and tetrahydrothiopyranyl, which is unsubstituted or substituted with 1-3 substituents independently selected from:

-   -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3         substituents where the substituents are independently selected         from:         -   (i) halo, and         -   (ii) phenyl,     -   (b) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl and pyrazinyl,     -   (c) —CO₂R⁹, wherein R⁹ is selected from:         -   (i) hydrogen, and         -   (ii) —C₁₋₄alkyl.     -   (d) hydroxy, and     -   (e) oxo.

In an embodiment of the present invention, R^(3a) and R^(3b) and the carbon atom(s) to which they are attached are joined together to form a ring selected from piperidinyl, cyclohexyl, tetrahydropyranyl, and tetrahydrothiopyranyl, which ring is unsubstituted or substituted with 1-3 substituents each independently selected from:

-   -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3         substituents independently selected from: fluoro and phenyl,     -   (b) —CO₂—C₁₋₄alkyl,     -   (c) hydroxyl, and     -   (d) oxo.

In an embodiment of the present invention A¹ is a bond.

In an embodiment of the present invention A² is —CH₂—.

In an embodiment of the present invention J is selected from: ═C(R^(6a))—; and —CH₂—; wherein R^(6a) is defined herein.

In an embodiment of the present invention J is —CH₂—.

In an embodiment of the present invention J is ═C(R^(6a))—; wherein R^(6a) is defined herein.

In an embodiment of the present invention K is selected from: ═C(R^(6b))—; —CH₂—; and —C(═O)—; wherein R^(6b) is defined herein.

In an embodiment of the present invention K is —CH₂—.

In an embodiment of the present invention K is ═C(R^(6b))—; wherein R^(6b) is defined herein.

In an embodiment of the present invention R⁴ is selected from: hydrogen and —C₁₋₆alkyl, which is unsubstituted or substituted with fluoro.

In an embodiment of the present invention R⁴ is hydrogen.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) are independently selected from hydrogen, C₁₋₆alkyl and halo.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) are independently selected from hydrogen and halo.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) are hydrogen.

In an embodiment of the present invention R^(6a) and R^(6b) are independently selected from:

-   -   (1) hydrogen;     -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3         substituents each independently selected from: halo,         —O—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and phenyl,     -   (3) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,         tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or         heterocycle is unsubstituted or substituted with 1-3         substituents where the substituents are each independently         selected from: —C₁₋₄alkyl which is unsubstituted or substituted         with 1-3 fluoro, —O—C₁₋₄alkyl, which is unsubstituted or         substituted with 1-3 fluoro, halo and hydroxyl,     -   (4) halo,     -   (5) —NR¹⁰R¹¹,     -   (6) hydroxy,     -   (7) —O—C₁₋₄alkyl which is unsubstituted or substituted with 1-3         halo.

In an embodiment of the present invention R^(6a) and R^(6b) are independently selected from:

-   -   (1) hydrogen;     -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3         fluoro, and     -   (3) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,         tetrahydrofuryl, piperidinyl, and morpholinyl.

In an embodiment of the present invention R^(6a) and R^(6b) and the atom(s) to which they are attached are joined to form a ring selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl and thienyl, which ring is unsubstituted or substituted with 1-3 substituents each independently selected from:

-   -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3         substituents each independently selected from: halo,         —O—C₁₋₆alkyl, —CO₂R⁹, —NR¹⁰R¹¹ and CONR^(10a)R^(11a),     -   (b) phenyl or heterocycle, wherein heterocycle is selected from:         pyridyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl,         piperidinyl and morpholinyl, which phenyl or heterocycle is         unsubstituted or substituted with 1-3 substituents each         independently selected from: —C₁₋₄alkyl, which is unsubstituted         or substituted with 1-5 fluoro, —O—C₁₋₄alkyl, which is         unsubstituted or substituted with 1-3 fluoro, halo and hydroxyl,     -   (c) halo,     -   (d) hydroxy,     -   (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5         halo,     -   (f) —CN,     -   (g) —NR¹⁰R¹¹,     -   (h) —CONR^(10a)R^(11a), and     -   (i) oxo.

In an embodiment of the present invention R^(6a) and R^(6b) and the atom(s) to which they are attached are joined to form a ring selected from phenyl, pyridyl, and pyrimidinyl, which ring is unsubstituted or substituted with 1-3 substituents each independently selected from: —C₁₋₄alkyl which is unsubstituted or substituted with 1-3 fluoro, halo, hydroxy and —O—C₁₋₄alkyl.

In an embodiment of the present invention R^(6a) and R^(6b) and the atom(s) to which they are attached are joined to form a ring selected from pyridyl, and pyrimidinyl.

In an embodiment of the present invention m is 1.

In an embodiment of the present invention n is 1.

In an embodiment of the present invention n is 2.

It is to be understood that where one or more of the above recited structures or substructures recite multiple substituents having the same designation each such variable may be the same or different from each similarly designated variable. The invention is not limited to structures and substructures wherein each instance of a particular variable must represent the same moiety or substructure.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of the R^(10a) and R^(11a) substituents are capable of forming a ring structure. Moreover, even those substituents capable of ring formation may or may not form a ring structure.

Also as appreciated by those of skill in the art, halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclic structures having no double or triple bonds. Thus C₁₋₆alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C₁₋₆alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which which forms a ring of three or more atoms. C₀ or C₀alkyl is defined to identify the presence of a direct covalent bond.

As used herein, “aryl” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except where noted, represents a stable 5- to 7-membered monocyclic- or stable 8- to 11-membered bicyclic heterocyclic ring system which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazolidinone, imidazoline, imidazolinone, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane, 2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine, 2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran, tetrahydropyran, thiamorpholine, thiazoline, thiazolidine, thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents a stable 4- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxides thereof.

The term “alkoxy,” as in C₁-C₆ alkoxy, is intended to refer to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched and cyclic configuration. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The terms “bond” and “absent” are in certain instances herein used interchangeably to refer to an atom (or chemical moiety) which is not present in a particular embodiment of the invention. In such embodiments, the atoms adjacent the “bond” or “absent” atom are simply bonded to one another. For example, in certain embodiments of the invention described and claimed herein, where A² is described as “absent”. In such a molecule, it is understood that A¹ is bonded directly to the —C(═O) moiety, resulting in the sub-structure B⁴-A¹-C(═O). The absence of a specific atom or moiety, particularly an atom or moiety which serves to link or connect other atoms or moieties, does not imply that such other atoms or moieties are not linked.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. In one aspect of the invention the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. Specific compounds within the present invention include a compound which is selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRP receptors in a patient such as a mammal in need of such antagonism comprising the administration of an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.

Another embodiment of the present invention is directed to a method for the treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired. The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. As used herein, the term “treatment” refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.

The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention as antagonists of CGRP receptor activity may be demonstrated by methodology known in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptors and functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors in SK—N-MC cell membranes was carried out essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, membranes (25 □g) were incubated in 1 ml of binding buffer [10 mM BEPES, pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 μM ¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h, the assay was terminated by filtration through GFB glass fibre filter plates (Millipore) that had been blocked with 0.5% polyethyleneimine for 3 h. The filters were washed three times with ice-cold assay buffer, then the plates were air dried. Scintillation fluid (50 □l) was added and the radioactivity was counted on a Topcount (Packard Instrument). Data analysis was carried out by using Prism and the K_(i) was determined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973) Biochein. Pharmacol. 22, 3099-3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK—N-MC cells were grown in minimal essential medium (MEM) supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100 units/ml penicillin and 100 □g/ml streptomycin at 37° C., 95% humidity, and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in 96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for ˜18 h before assay. Cells were washed with phosphate-buffered saline (PBS, Sigma) then pre-incubated with 300 □M isobutylmethylxanthine in serum-free MEM for 30 min at 37° C. Antagonist was added and the cells were incubated for 10 min before the addition of CGRP. The incubation was continued for another 15 min, then the cells were washed with PBS and processed for cAMP determination according to the manufacturer's recommended protocol. Maximal stimulation over basal was defined by using 100 nM CGRP. Dose-response curves were generated by using Prism. Dose-ratios (DR) were calculated and used to construct full Schild plots (Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48-58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) was subcloned into the expression vector pIREShyg2 (BD Biosciences Clontech) as a 5′NheI and 3′ PmeI fragment. Human RAMP1 (Genbank accession number AJ001014) was subcloned into the expression vector pMSpuro2 (BD Biosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (human embryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/ml streptomycin, and maintained at 37° C. and 95% humidity. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in BBSS. Stable cell line generation was accomplished by co-transfecting 10 ug of DNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks. CRLR and RAMP1 expression constructs were co-transfected in equal amounts. Twenty-four hours after transfection the cells were diluted and selective medium (growth medium+300 ug/ml hygromycin and 1 ug/ml puromycin) was added the following day. A clonal cell line was generated by single cell deposition utilizing a FACS Vantage SE (Becton Dickinson). Growth medium was adjusted to 150 ug/ml hygromycin and 0.5 ug/ml puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant human CRLR/RAMP1 were washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors (Roche). The cell suspension was disrupted with a laboratory homogenizer and centrifuged at 48,000 g to isolate membranes. The pellets were resuspended in harvest buffer plus 250 mM sucrose and stored at −70° C. For binding assays, 10 ug of membranes were incubated in 1 ml binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours at room temperature containing 10 pM ¹²⁵I-hCGRP (Amersham Biosciences) and antagonist. The assay was terminated by filtration through 96-well GFB glass fiber filter plates (Millipore) that had been blocked with 0.05% polyethyleneimine. The filters were washed 3 times with ice-cold assay buffer (10 mM HEPES, pH 7:4). Scintillation fluid was added and the plates were counted on a Topcount (Packard). Non-specific binding was determined and the data analysis was carried out with the apparent dissociation constant (K_(i)) determined by using a non-linear least squares fitting the bound CPM data to the equation below: $Y_{\underset{\_}{obsd}} = \frac{\begin{matrix} {{\left( {Y_{\max} - Y_{\min}} \right)\left( {{\% I_{Max}} - {\%_{I\quad\min}/100}} \right)} + Y_{\min} +} \\ {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\%\quad{I_{\max}/100}}} \right)} \end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {{+ \lbrack{Radiolabel}\rbrack}/K_{d}} \right)}^{nH}} \right.}$ Where Y is observed CPM bound, Y_(max) is total bound counts, Y min is non specific bound counts, (Y max−Y min) is specific bound counts, % I max is the maximum percent inhibition, % 1 min is the minimum percent inhibition, radiolabel is the probe, and the K_(d) is the apparent dissociation constant for the radioligand for the receptor as determined by Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in complete growth medium at 85,000 cells/well in 96-well poly-D-lysine coated plates (Corning) and cultured for 19 h before assay. Cells were washed with PBS and then incubated with inhibitor for 30 min at 37° C. and 95% humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech, Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was added to the cells at a concentration of 3000M and incubated for 30 min at 37° C. Human O-CGRP was added to the cells at a concentration of 0.3 nM and allowed to incubate at 37° C. for 5 min. After O-CGRP stimulation the cells were washed with PBS and processed for cAMP determination utilizing the two-stage assay procedure according to the manufacturer's recommended protocol (cAMP SPA direct screening assay system; RPA 559; Amersham Biosciences). Dose response curves were plotted and IC₅₀ values determined from a 4-parameter logistic fit as defined by the equation y=((a−d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response, d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity as antagonists of the CGRP receptor in the aforementioned assays, generally with a K₁ or IC₅₀ value of less than about 50 □M. Such a result is indicative of the intrinsic activity of the compounds in use as antagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also include therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with an an anti-migraine agent, such as ergotamine and dihydroergotamine, or other serotonin agonists, especially a 5-HT_(1B/1D) agonist, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan, a 5-HT_(1D) agonist such as PNU-142633 and a 5-HT_(1F) agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine and the like; or glucocorticoids. Similarly, the instant compounds may be administered with an analgesic such as aspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with an interleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1 receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT₂ receptor antagonists; opiod agonists such as codeine, hydrocodone, tramadol, dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist or potentiator; a GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; an antidepressant, for example amitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene antagonist, for example montelukast or zafirlukast; an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide.

Also, the present compounds may be used in conjunction with gap junction inhibitors; neuronal calcium channel blockers such as civamide; AMPA/KA antagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergocomine, dihydroergocristine, dihydroergocryptine, dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with a beta-adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochliorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine, gabapentin, pregabalin or divalproex sodium; an anti-hypertensive such as an angiotensin II antagonist, for example losartan, irbesartin, valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartan and candesartan cilexetil, an angiotensin I antagonist, an angiotensin converting enzyme inhibitor such as lisinopril, enalapril, captopril, benazepril, quinapril, perindopril, ramipril and trandolapril; or botulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non-sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine, phenylpropanolamine, or pseudoephedrine. The present compounds also may be used in conjunction with anti-emetics.

In a particularly preferred embodiment the present compounds are used in conjunction with an anti-migraine agent, such as: ergotamine or dihydroergotamine; a 5-HT₁ agonist, especially a 5-HT_(1B/1D) agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, and other serotonin agonists; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the other active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s), and via the same or different routes of administration.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals the compounds of the invention are effective for use in humans.

The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. Similarly, transdermal patches may also be used for topical administration.

The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require antagonism of CGRP receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing the risk of headache, migraine, cluster headache, or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein.

The compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.

The synthesis of aniline intermediates may be conducted as described in Schemes 1-5. Aniline intermediates bearing R^(5a), R^(5b) and R^(5c) may be prepared by employing appropriately substituted starting materials or by derivatization of any intermediates and/or final products as desired by methods known in the art.

The synthesis of a representative spirolactam aniline (6) is illustrated in Scheme 1. The known ethyl indane-2-carboxylate (1, Schaaf et al., J. Med. Chem. 1983, 26, 328-334) may be alkylated with allyl bromide and sodium bis(trimethylsilyl)amide to form 2. Oxidation of the allyl group with ozone can produce the aldehyde 3, which cyclizes to the lactam 4 after treatment with ammonium acetate and sodium cyanoborohydride and heating in toluene. The reductive amination of aldehyde 3 with amines other than ammonia may be used to provide a variety of N-protected analogues of lactam 4, which may facilitate subsequent chemical steps prior to removal of the lactam protecting group. The intermediate lactam may be nitrated, for example using 70% nitric acid, and the resulting nitro compound 5 can be reduced to provide the aniline intermediate 6, using a variety of well known methodologies, such as catalytic hydrogenation. Those skilled in the art of organic synthesis will recognize that straightforward modifications of this methodology may be used to access other spirolactam intermediates, such as those with other lactam ring sizes. Additionally, use of an alternative starting material to the indane 1 may be used to provide different products, such as tetralin-based spirolactams.

In Scheme 2, an example of the synthesis of a spirooxindole intermediate is shown. Treatment of oxindole (7) with butyllithium and tetramethylethylenediamine, followed by a dihalide or its equivalent, e.g. 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533], leads to the spirooxindole 9. The bromide may be converted to a carboxylic acid (10) by treatment with ethylmagnesium bromide and tert-butyllithium, and quenching of the resulting organolithium species with carbon dioxide. A Curtius rearrangement using diphenylphosphoryl azide in tert-butanol, followed by deprotection with hydrochloric acid can provide the aniline 11. Alternative conditions, such as treatment of acid 10 with sodium azide in concentrated sulfuric acid, may also be used to provide aniline 11.

Scheme 3 illustrates a route to spiroimide derivative 16, using methodology that is similar to that shown in Scheme 1. Ethyl indane-2-carboxylate (1) may be alkylated with tert-butyl bromoacetate to form the diester 12. Subjection of 12 to basic, then acidic hydrolysis conditions can provide the diacid 13. Treatment of the diacid 13 with a number of different reagents can provide imide 14 or a derivative thereof. In Scheme 3, heating 13 in the presence of acetyl chloride, followed by reaction with ammonia affords spiroimide 14. Reaction with sodium nitrite in trifluoroacetic acid, followed by hydrogenation over palladium can provide the aniline 16.

A representative synthesis of a spiroazaoxindole intermediate is shown in Scheme 4. 7-Azaindole (17) may be protected with a variety of protecting groups, such as the (trimethylsilyl)ethoxymethyl group shown in Scheme 4. Following the method of Marfat and Carter (Tetrahedion Lett., 1987, 28, 4027-4030), treatment of 18 with pyridine hydrobromide perbromide provides the dibromoazaoxindole 19, which may be reduced to the corresponding azaoxindole 20 by reaction with zinc. The key alkylation of 20 with 1,2-bis(bromomethyl)-4-nitrobenzene (21, Cava et al., J. Org. Chem. 2000, 65, 5413-5415) is carried out using cesium carbonate in DMF to afford the spiroazaoxindole 22. A variety of other bases and solvents may be employed in this alkylation reaction, and use of an alternative alkylating agent to the dibromide shown here can lead to different products. Reduction of the nitro compound 22, for example using hydrogenation over palladium, and a two-step deprotection affords the corresponding aniline 24. The methodology shown in Scheme 4 is not limited to azaoxindoles such as 20, but may be applied to a variety of suitably protected heterocyclic systems to give the corresponding spiro compounds.

Spiroazaoxindole intermediates, such as those illustrated in Scheme 4, may be resolved to give pure enantiomers using techniques familiar to those skilled in the art. For example, chromatography of the protected intermediate 23 on a ChiralPak OD column can be used to provide the individual enantiomers (+)-23 and (−)-23, and these enantiomers may be converted to the corresponding anilines [(+)-24 and (−)-24] by the two-step deprotection. In the case of compound 24, the dextro isomer is the (R)-enantiomer and the levo isomer (S)-enantiomer, i.e. (+)-24 is (R)-24 and (−)-24 is (S)-24. Use of standard coupling procedures using enantiomerically pure anilines can provide the individual enantiomers of the final products. Resolution may be effected by other methodologies, such as fractional crystallization of diastereomeric salts, and it may be carried out on other synthetic intermediates or on the final products. Alternatively, an asymmetric synthesis of a key intermediate could be used to provide an enantiomerically enriched final product.

As an example of related methodology to that described in Scheme 4, using alternative conditions for the alkylation reaction, the synthesis of spirodiazaoxindole compounds is outlined in Scheme 5. Published methodology is used to convert 6-chloro-deazapurine into 4-chloro-diazaoxindole 25, the starting material in Scheme 5 (Sun et al., Biorg Med. Chem Lett. 2002, 12, 2153-2157).

Alkylation with dibromide 21 under similar conditions to that shown in Scheme 2 may provide the spirodiazaoxindole 26. Hydrogenation at 30 psi for two hours can provide the aniline 27, while hydrogenation at higher pressure (55 psi) and longer reaction time (180 hours) can provide the des-chloroanalogue 28.

Aniline intermediates, such as those described in Schemes 1-5, may be coupled with a variety of carboxylic acids, or carboxylic acid derivatives, to provide amide final products.

Thus, coupling of amine A with a carboxylic acid, R′CO₂H, can be used to give amide B. Other standard coupling conditions may be employed in the synthesis of such amides, such as use of an alternative coupling reagent like PyBOP, or activation of the carboxylic acid as an acid anhydride or acid chloride. Ureas may also be synthesized from aniline A and an appropriate amine by use of phosgene, 1,1′-carbonyldiimidazole, 4-nitrophenyl chloroformate, or a similar reagent.

Most of the acids (R′CO₂H), used to make the compounds of the present invention are readily available. They may be obtained from commercial sources or synthesized by methodology familiar to those skilled in the art and as described in the chemical literature. A number of the acids were synthesized using the methodology outlined in Schemes 7-14.

In Scheme 7, carbonylation of a 2-aminophenol (C) with 1,1′-carbonyldiimidazole affords the benzoxazolone D, which is treated with sodium hydride, then tert-butyl bromoacetate, to provide ester E. Standard deprotection using trifluoroacetic acid affords the acid intermediate F, which may be used for coupling to amines like A to give compounds of the present invention.

Scheme 8 illustrates a general route to substituted benzimidazolone derivatives. Simple alkylation of the benzimidazolone G affords the acetate derivative H, which may be separated from any bis-alkylated material by chromatography. For a variety of aryl or heteroaryl R₁, reaction of the corresponding bromide (R₁Br) with H using copper catalysis provides the N,N-disubstituted intermediate I. The tert-butyl ester I may be deprotected under acidic conditions to give J, which is readily converted to the final products. The chemistry in Scheme 8 may be modified in a number of ways. For example, use of alternative conditions for the key transformation of H to I can permit a variety of R₁ substituents to be introduced. Examples of such alternative conditions include a palladium-catalyzed coupling with H, or an alkylation or arylation of the anion of H under basic conditions, for example using sodium hydride followed by R₁Cl. Further chemical manipulation of the substituents R₁ and R₂ is also understood to be within the scope of this invention. Either R₁ or R₂ may be modified under a variety of conditions at one or more intermediate steps in the synthetic sequence to afford a diverse group of final products. An example of this strategy is shown in Scheme 9.

In Scheme 9, benzimidazolone G is reacted with 2,4-dibromothiazole to give bromothiazole K. Displacement of the bromide in K with thiomethoxide affords intermediate L, which may be alkylated to give ester M in analogy with other schemes shown herein. Subjection of M to oxidative conditions, such as use of OXONE®, can provide the corresponding sulfoxide, which may be deprotected to give acid N. Slight modifications of these conditions could be applied to afford the corresponding sulfide or sulfoxide analogues.

In Scheme 10, another route to the substituted benzimidazolone J is shown. In this route, an amine (RINH₂) is condensed with a 2-chloronitroarene derivative (P) to give amine Q. The nitro group may be reduced, for example under catalytic hydrogenation conditions, to give the corresponding aniline, and this may be treated with triphosgene to afford the benzimidazolone R. Elaboration of R in analogy with the earlier Schemes leads to the desired acid intermediate J. In a simple variation of this methodology, the arene P may be replaced with a heterocycle, such as 2-chloro-3-nitropyridine to afford an aza analogue of J.

In Scheme 11, a route to regiospecifically-substituted benzimidazolone intermediate H from the corresponding anthranilic acid is shown. Treatment of the anthranilic acid T with phosgene can lead to the benzoxazinedione U. Alkylation of U with tert-butyl bromoacetate, followed by opening of the benzoxazinedione ring with NaOH, provides the alkylated anthranilic acid V. Treatment of acid V with diphenylphosphoryl azide leads to a Curtius rearrangement in which the intermediate isocyanate is trapped to give the benzimidazolone H. This route offers a method of installing the R₂ substituent(s) in positions dictated by the substitution pattern of the anthranilic acid starting material.

A synthesis of N-spirooxindole acetic acids is outlined in Scheme 12. Following chemistry described in U.S. Pat. No. 5,849,780 A (1998), an example of such begins with the alkylation of oxindole (W) with a halide or its equivalent, e.g. 2-(2-bromoethoxy)tetrahydro-2H-pyran, and a base, such as potassium tert-butoxide or butyllithium, to yield intermediate X. Treatment with bromine produces the tribromide Y, which when reacted with sodium sulfide can give the spirooxindole Z. Alternatively, W could be alkylated with a dihalide or other bis-alkyating agent, e.g. 2-iodoethyl ether, to produce a spirooxindole directly. Alkylation of oxindole Z with ethyl bromoacetate followed by hydrolysis affords the desired acid intermediate BB. Further chemical manipulation of substituents on the aryl ring is understood to be within the scope of this invention. An example of this strategy is shown in the last step when the bromide is removed by treatment with ethylmagnesium bromide and tert-butyllithium to produce carboxylic acid CC.

Another method for synthesizing spiroxoindoles is outlined in Scheme 13, in which W is initially trialkylated with methyl acrylate according to chemistry described in U.S. Pat. No. 6,573,386 B1 (2001). In the same reaction flask, the intermediate then undergoes a Dieckmann condensation, N-dealkylation, and decarboxylation to produce spirocyclohexanone DD. Further manipulation as described in previous schemes may be used to produce carboxylic acid intermediates like FF.

Scheme 14 illustrates a general route to substituted indole acetic acids. Substituted indoles (GG) can be converted to indole acetonitriles (II) via a two step sequence: alkylation with N,N,N′,N′-tetramethylmethanediamine followed by displacement with potassium cyanide. Alternatively, the first intermediate (HH) can be formed by reaction of indole GG with dimethylamine and formaldehyde in a microwave reactor. Treatment with hydrochloric acid in methanol can convert the nitrile to the methyl ester JJ. Further manipulation in analogy with previous schemes can produce carboxylic acid intermediates like LL. Azaindole acetic acids may also be synthesized via a similar scheme starting with an appropriately substituted azaindole.

Simple modifications of these routes, including different protecting group strategies, application of well-precedented methodology, and the use of heterocycles and reagents other than those described in the foregoing Schemes, may be used to provide other acids of interest, such as those detailed in Intermediates 24-36 (vide infra).

In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.

In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

Intermediate 1

(±)-5-Amino-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one Step A. Ethyl 2-allylindane-2-carboxylate

To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium his(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) drop wise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 minutes. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH₄Cl (50 mL) and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH₄Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 75:25, to give the title compound. MS: m/z=231 (M+1).

Step B. Ethyl 2-(2-oxoethyl)indane-2-carboxylate

Ethyl 2-allylindane-2-carboxylate from Step A (3.00 g, 13.0 mmol) was dissolved in CH₂Cl₂ (100 mL) and cooled to −78° C. Ozone was bubbled through the solution for 15 minutes, at which time a light blue color persisted. Triethylamine (3.63 mL, 26.1 mmol) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was partitioned between saturated NaHCO₃ (100 mL) and CH₂Cl₂ (100 mL). The aqueous phase was further extracted with CH₂Cl₂ (2×50 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=233 (M+1).

Step C. 1,3-Dihydro-2′H-spiro[indene-23′-pyrrolidin]-2′-one

Ethyl 2-(2-oxoethyl)indane-2-carboxylate from Step B (3.03 g, 13.0 mmol) and ammonium acetate (50.2 g, 651 mmol) were stirred in AcOH (20 mL) and MeOH (20 mL) at ambient temperature for 4 h, then sodium cyanoborohydride (1.29 g, 19.5 mmol) was added and stirring continued for 16 h. The reaction mixture was concentrated in vacuo and partitioned between saturated NaHCO₃ (50 mL) and CH₂Cl₂ (50 mL). The aqueous phase was further extracted with CH₂Cl₂ (2×25 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield a yellow oil. The crude oil was heated to reflux in toluene (100 mL) for 1.5 h and then concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=188 (M+1).

Step D. (±)-5-Nitro-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one

To 1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one from Step C (114 mg, 0.609 mmol) cooled in an ice bath was added 70% HNO₃ (5 mL). The reaction mixture was stirred for 45 min, diluted with H₂O (10 mL), and extracted with CH₂Cl₂ (3×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=233 (M+1).

Step E. (±)-5-Amino-1,3-dihydro-2′H-spiro[indene-23′-pyrrolidin]-2′-one

To a solution of (±)-5-nitro-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one from Step D (97.0 mg, 0.418 mmol) in MeOH(5 mL) was added 10% Pd/C (15 mg). The reaction mixture was stirred under a hydrogen atmosphere (ca. 1 atm) for 1.5 h, then filtered through a Celite pad and concentrated under reduced pressure to give the title compound. MS: m/z=203 (M+1).

Intermediate 2

(±)-5-Amino-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one Step A. (±)-5-Bromo-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one

To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL) was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) drop wise, followed by the drop wise addition of tetramethylethylenediamine (0.905 mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then a solution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) was added drop wise. The reaction solution was stirred at −10 to −20° C. for 2 h and at ambient temperature for 16 h. The reaction mixture was partitioned between saturated NH₄Cl (50 mL) and EtOAc (50 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=315 (M+1).

Step B. (±)-2′-Oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3°-indole]-5-carboxylic acid

To a solution of (±)-5-bromo-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one from Step A (220 mg, 0.700 mmol) in THF (2 mL) was added ethylmagnesium bromide (3.0 M in ether, 0.467 mL, 1.40 mmol) drop wise, maintaining the reaction temperature <−60° C. Then tert-butyllithium (1.7 M in pentane, 1.65 mL, 2.80 mmol) was added drop wise, maintaining the reaction temperature <−60° C. The reaction solution was stirred for 5 min at −78° C., then CO₂(g) was bubbled through the solution for 15 min. H₂O (5 mL) was added and the solution was warmed to ambient temperature. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO₃ (20 mL). The organic layer was further extracted with saturated NaHCO₃ (2×10 mL). The combined aqueous layers were washed with EtOAc (10 mL) and then acidified with 12M HCl. The combined aqueous layers were extracted with CH₂Cl₂ (5×10 mL). A white precipitate formed that was insoluble in either layer, and was collected by filtration. The combined CH₂Cl₂ layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. This crude product was combined with the recovered precipitate to give the title compound. MS: m/z=280 (M+1).

Step C. (±)-tert-Butyl (2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)carbamate

A solution of (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indole]-5-carboxylic acid from Step B (65.0 mg, 0.233 mmol), diphenylphosphoryl azide (0.060 mL, 0.279 mmol), and triethylamine (0.039 mL, 0.279 mmol) in t-BuOH (5 mL) was heated to reflux for 3 h. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=295 (M-C₄H₇).

Step D. (±)-5-Amino-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one

HCl(g) was bubbled through a solution of (±)-tert-butyl (2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)carbamate from Step C (19.0 mg, 0.054 mmol) in EtOAc (5 mL) for 15 min. The reaction mixture was stirred at ambient temperature for 1 h and then concentrated in vacuo to give the title compound as the hydrochloride salt. MS: m/z=251 (M+1).

Intermediate 3

(±)-5-Amino-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione Step A. Ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate

To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (2.00 g, 10.5 mmol) in TIE at −78° C. was added sodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF, 15.8 mmol) drop wise over 10 min. The mixture was stirred for 15 min, then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added drop wise over 30 min. The resulting mixture was stirred for 30 min at −78° C., then poured into brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 90:10, to give the title compound. MS: m/z=368 (M+Na+CH₃CN).

Step B. 2-(2-tert-Butoxy-2-oxoethyl)indane-2-carboxylic acid

A mixture of ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate from Step A (2.48 g, 8.15 mmol) and 1.0 N sodium hydroxide (8.96 mL, 8.96 mmol) in THF (50 mL), H₂O (10 mL), and EtOH (20 mL) was stirred at ambient temperature for 18 h. The mixture was acidified with hydrochloric acid to about pH 3 and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=340 (M+Na+CH₃CN).

Step C. (Carboxymethyl)indane-2-carboxylic acid

A solution of 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylic acid from Step B (1.50 g, 5.43 mmol) in EtOAc (100 mL) was saturated with HCl (g) and aged at ambient temperature for 1 h, then concentrated to dryness in vacuo to give the title compound. MS: 7 m/z=284 (M+Na+CH₃CN).

Step D. 1,3-Dihydro-2H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione

A solution of 2-(carboxymethyl)indane-2-carboxylic acid from Step C (1.10 g, 4.99 mmol) in acetyl chloride (18 mL) was heated at reflux for 18 h, then concentrated in vacuo. The residue was recrystallized from toluene to give 1′,3′-dihydrospiro[furan-3,2′-indene]-2,5(4H)-dione as an ivory solid. This solid was dissolved in CH₂Cl₂ (25 mL) and NH₃ (g) was bubbled into the mixture for 20 min. After a further 30 min, the solvent was evaporated under reduced pressure. The resulting solid was dried under high vacuum for 1 h, then resuspended in acetyl chloride (20 mL) and heated to reflux for 18 h. The solvent was removed in vacuo and the crude solid was recrystallized from EtOH:Et₂O to afford the title compound. MS: m/z=202 (M+1).

Step E. (±)-5-Amino-1,3-dihydro-2′H,5H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione

To a solution of 1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione from Step D (400 mg, 1.99 mmol) in CF₃CO₂H (10 mL) was added sodium nitrite (411 mg, 5.96 mmol) and the mixture was heated to 55° C. for 2 h. The mixture was cooled and diluted with H₂O (10 mL), then extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo, to give 5-nitro-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione, which contained some of the isomeric 4-nitro-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione. This solid was dissolved in EtOH (30 mL), then AcOH (0.55 mL) and 10% Pd/C (55 mg) were added. The mixture was stirred vigorously under an atmosphere of hydrogen (ca. 1 atm) for 2 h, then filtered through a pad of Celite, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc—95:5 to 10:90, to give the title compound. MS: m/z=217 (M+1).

Intermediate 4

(−)-5-Amino-1,3-dihydrospiro[indene-2,3°-pyrrolo[2,3-b]pyridin]-2′(1′H)-one Step A. 1-{[2-Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) was added in portions over 25 min to a solution of 7-azaindole (39.8 g, 0.337 mol) in DMF (200 mL) at 0 □C and the mixture was stirred for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was then added slowly over 15 min, keeping the temperature of the reaction mixture below 10 □C. After 1 h, the reaction was quenched with H₂O (500 mL) and the mixture was extracted with CH₂Cl₂ (5×300 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered, concentrated, and dried under high vacuum to give the title compound. MS: m/z=249 (M+1).

Step B. 3,3-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine from Step A (43.1 g, 0.174 mol) in dioxane (300 mL) was added dropwise over 30 min to a suspension of pyridine hydrobromide perbromide (277 g, 0.868 mol) in dioxane (300 mL). The reaction was stirred at ambient temperature using an overhead mechanical stirrer. After 60 min, the biphasic reaction mixture was quenched with H₂O (300 mL) and extracted with EtOAc (300 mL). The aqueous layer was washed with EtOAc (2×300 mL) and the combined organic layers were washed with H₂O (4×300 mL; the final wash was pH 5-6), then brine (300 mL), then dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was immediately dissolved in CH₂Cl₂ and the solution filtered through a plug of silica, eluting with CH₂Cl₂ until the dark red color had completely eluted from the plug. The filtrate was washed with saturated aqueous NaHCO₃ (400 mL), then brine (400 mL), dried over MgSO₄ and concentrated in vacuo to give the title compound. MS: m/z=423 (M+1).

Step C. 1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Zinc (100 g, 1.54 mol) was added to a solution of 3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step B (65 g, 0.154 mol) in THF (880 mL) and saturated aqueous NH₄Cl (220 mL). After 3 h, the reaction was filtered and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H₂O (500 mL), which resulted in the formation of a white precipitate. Both layers were filtered through a Celite pad and the layers were separated. The aqueous layer was further extracted with EtOAc (2×200 mL) and the combined organic layers were washed with H₂O (100 mL), dried over MgSO₄, filtered, and concentrated. The crude product was filtered through a plug of silica gel, eluting with EtOAc:CH₂Cl₂-10:90, and the eluant was concentrated under reduced pressure to provide the title compound. MS: m/z=265 (M+1).

Step D. (4-Nitro-1,2-phenylene)dimethanol

A solution of 4-nitrophthalic acid (40.0 g, 189.5 mmol) in THF (500 mL) was added drop wise over 1.5 h to a solution of borane-THF complex (1 M, 490 mL, 490 mmol), maintaining the reaction temperature between 0 □C and 5 □C. After the addition, the reaction was allowed to warm slowly to ambient temperature and stirred for 18 h. MeOH (100 mL) was added carefully and the precipitated solid dissolved. The mixture was concentrated in vacuo to about 500 mL, cooled to 0 □C, and 10 N NaOH was added to adjust the pH to 10-11. This mixture was extracted with EtOAc (3×600 mL) and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound. MS: m/z=207 (M−OH+CH₃CN).

Step E. 1,2-Bis(bromomethyl)-4-nitrobenzene

Phosphorus tribromide (3.90 mL, 41.1 mmol) in Et₂O (50 mL) was added drop wise over 1.5 h to a solution of (4-nitro-1,2-phenylene)dimethanol from Step D (6.85 g, 37.4 mmol) in Et₂O (150 mL). After 18 h, the reaction mixture was cooled to 0 □C and quenched with H₂O (25 mL). The layers were separated and the organic layer was washed with H₂O, then saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, and concentrated to give the title compound. MS: m/z=309 (M).

Step F. (±)-5-Nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene from Step E (40.9 g, 132 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step C (31.5 g, 119 mmol) in DMF (2 L) was added cesium carbonate (129 g, 397 mmol) portion wise, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H₂O (1 L). The organic layer was washed with H₂O (1 L), then brine (500 mL), then dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=412 (M+1).

Step G. (−)-5-Amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of 10% Pd/C (3 g) and 5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step F (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL) under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture was filtered through a pad of Celite, washing extensively with MeOH, and the filtrate was concentrated to give the crude racemic compound. The enantiomers were resolved by HPLC, utilizing a Chiralcel OD column and eluting with MeOH. The first major peak to elute was (−)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound, and the second major peak to elute was (+)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one. MS: m/z=382 (M+1).

Step H. (−)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A solution of (−)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step G (13.7 g, 35.9 mmol) in MeOH (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylene diamine (2.40 mL, 35.9 mmol) and 10 N NaOH (7.20 mL, 72.0 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H₂O (400 mL) and extracted with CHCl₃ (2×1 L). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (50 mL) to give the title compound. MS: m/z=252 (M+1).

Intermediate 5

(±)—S-Amino-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one Step A. 5,5-Dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Pyridine hydrobromide perbromide (15.6 g, 48.8 mmol) was added in three portions to a stirred solution of 6-chloro-7-deazapurine (2.50 g, 16.3 mmol) at 40° C. in tert-butanol (100 mL). After 3 h, an additional amount of pyridine hydrobromide perbromide (5.19 g, 16.3 mmol) was added. After a further 2 h, the reaction was concentrated in vacuo and partitioned between EtOAc (200 mL) and H₂O (200 mL). The aqueous solution was extracted with EtOAc (2×100 mL) and the combined organic layers were washed with H₂O (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=328 (M+1).

Step B. 4-Chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Zinc (6.05 g, 92.6 mmol) was added to a solution of 5,5-dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step A (3.03 g, 9.26 mmol) in THF (20 mL) and saturated aqueous NH₄Cl (5 mL). After 3 h, the reaction mixture was concentrated in vacuo and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=170 (M+1).

Step C. (±)-4′-Chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50.0 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′N,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91.0 mg, 0.295 mmol, described in Intermediate 4) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H₂O (2 mL) and the mixture was partitioned between EtOAc (50 mL) and H₂O (50 mL). The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317 (M+1).

Step D. (±)-5-Amino-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

To a solution of 4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one from Step C (400 mg, 1.26 mmol) in EtOAc (40 mL) and MeOH (10 mL) was added triethylamine (0.880 mL, 6.32 mmol). The mixture was hydrogenated at 50 psi hydrogen over 10% Pd/C (100 mg). After 24 h and 90 h, an additional amount of palladium on carbon (100 mg) was added to the reaction mixture and hydrogenation was continued for a total of 180 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=253 (M+1).

Intermediate 6

(±)-5-Amino-4′-chloro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

To a solution of (=)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′R)-one (40.0 mg, 0.126 mmol, described in Intermediate 5) in EtOAc (10 mL) was added triethylamine (0.026 mL, 0.189 mmol). The mixture was hydrogenated at 30 psi hydrogen over 10% Pd/C (10 mg). After 2 h, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=287 (M+1).

Intermediate 7

(2-Oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid Step A. tert-Butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

To a stirred mixture of 2-hydroxybenzimidazole (4.00 g, 29.8 mmol) and tert-butyl bromoacetate (5.53 g, 28.3 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.31 g of a 60% dispersion in mineral oil, 32.8 mmol). The mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO₃ and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H₂O (300 mL) and the organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=249 (M+1).

Step B. tert-Butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate

A mixture of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step A (1.75 g, 7.05 mmol), 2-bromopyridine (3.36 mL, 35.2 mmol), copper powder (1.57 g, 24.7 mmol), CuCl (140 mg, 1.41 mmol), and KOAc (2.08 g, 21.1 mmol) in pyridine (30 mL) was heated at 100° C. for 3 h. The cooled mixture was partitioned between EtOAc (150 mL) and 10% aqueous citric acid (100 mL) and the organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=326 (M+1).

Step C. (2-Oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid

A solution of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B (2.27 g, 6.98 mmol) in EtOAc (100 mL) at 0° C. was saturated with HCl (g). The mixture was aged at 0° C. for a total of 3 h, and was re-saturated with HCl every 30 min. The mixture was concentrated in vacuo to give the title compound. MS: m/z=270 (M+1).

Intermediate 8

(2-Oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid Step A. tert-Butyl[3-(6-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

To a solution of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (130 mg, 0.52 mmol, described in Intermediate 7) in DMF (0.7 mL) was added sodium hydride (15 mg of a 60% dispersion in mineral oil, 0.38 mmol). The mixture was stirred for 5 min, then 4,6-dichloropyrimidine (234 mg, 1.57 mmol) was added and argon was bubbled through the mixture for 5 min. The reaction mixture was heated at 140° C. for 10 min in a microwave reactor. The cooled mixture was partitioned between CHCl₃ (10 mL) and saturated aqueous NaHCO₃ (5 mL). The aqueous phase was extracted further with CHCd₃ (10 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 75:25, to give the title compound. MS: m/z=361 (M+1).

Step B. tert-Butyl (2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate

A mixture of tert-butyl[3-(6-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (260 mg, 0.720 mmol), 10% Pd/C (23 mg) and triethylamine (0.150 mL, 1.08 mmol) in EtOH (5 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 2 h. The mixture was filtered through a pad of Celite, washing with EtOH, and the filtrate was concentrated to give the title compound. MS: m/z=327 (M+1).

Step C. (2-Oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid

Essentially following the procedures described for Intermediate 7, but using tert-butyl (2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=271 (M+1).

Intermediate 9

[3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid Step A. 4,6-Dimethyl-1,3-dihydro-2H-benzimidazol-2-one

A mixture of 4,6-dimethyl-2-nitroaniline (10.0 g, 60.2 mmol) and 10% Pd/C (1.0 g) in EtOH (300 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 3 h, then filtered through a Celite pad and concentrated in vacuo. The crude solid was dissolved in CH₃CN (200 mL) and triphosgene (15.0 g, 50.5 mmol) was added. The mixture was stirred for 1 h, then H₂O (200 mL) was added slowly and stirring was continued for 1 h. The precipitate was isolated by filtration and dried to give the title compound. MS: m/z=163 (M+1).

Step B. tert-Butyl (4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

To a stirred solution of 4,6-dimethyl-1,3-dihydro-2H-benzimidazol-2-one from Step A (7.15 g, 44.1 mmol) in DMF (200 mL) was added sodium hydride (1.76 g of a 60% dispersion in mineral oil, 44.1 mmol) over 2 min. The mixture was stirred for 20 min, then tert-butyl bromoacetate (8.17 g, 41.9 mmol) in DMF (40 mL) was added and stirring was continued for 1 h. The reaction mixture was diluted with H₂O (400 mL) carefully and a solid precipitated. The mixture was aged for 5 min, then filtered to give a crude solid, which was purified by silica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc-100:0 to 40:60, to provide the title compound. MS: m/z=277 (M+1).

Step C. tert-Butyl[3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

To a solution of tert-butyl (4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B (100 mg, 0.36 mmol) in DMF (3 mL) was added sodium hydride (17 mg of a 60% dispersion in mineral oil, 0.43 mmol) followed by methyl bromoacetate (0.041 mL, 0.43 mmol) and the reaction mixture was stirred for 2 h. The reaction was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Lyophilization of the product-containing fractions afforded the title compound. MS: m/z=349 (M+1).

Step D. [3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid

Essentially following the procedures described for Intermediate 7, but using tert-butyl [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step C in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=293 (M+1).

Intermediate 10

{3-[2-(Dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid Step A. Methyl {3-[2-(dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate

A solution of [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (Intermediate 9) (305 mg, 1.04 mmol), N,N-dimethylamine hydrochloride (128 mg, 1.60 mmol), EDC (300 mg, 1.60 mmol), HOBT (240 mg, 1.60 mmol), and N, N-diisopropylethylamine (0.909 mL, 5.20 mmol) were stirred for 16 h at ambient temperature in DMF (3 mL). The mixture was partitioned between CH₂Cl₂ (10 mL) and saturated NaHCO₃ (10 mL) and the organic layer was dried over Na₂SO₄, filtered, and concentrated to give the compound. MS: m/z=320 (M+1).

Step B. {3-[2-(Dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid

Lithium hydroxide (131 mg, 3.12 mmol) was added to a solution of methyl {3-[2-(dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step A (333 mg, 1.04 mmol) in THF (3 mL) and H₂O (1 μL). After 72 h, H₂O was added and the precipitate was collected by filtration to give the title compound. MS: nil/z=306 (M+1).

Intermediate 11

2-Oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4°-piperidine]-1-acetic acid Step A. 1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidin]-2-one

A mixture of spiro[indoline-3,4′-piperidin]-2-one, [PCT Int. Appl. WO 0145707 A1 (2001)] trifluoroacetic acid salt (3.66 g, 11.6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.63 mL, 11.6 mmol), and triethylamine (8.06 mL, 57.9 mmol) in acetone (30 mL) was heated at reflux for 16 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH₂Cl₂ (50 mL) and washed with saturated aqueous NaHCO₃ (50 mL). The aqueous layer was further extracted with CH₂Cl₂ (2×25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=285 (M+1).

Step B. tert-Butyl 2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetate

To a stirred solution of 1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidin]-2-one from Step A (3.30 g, 11.6 mmol) in DMF (10 mL) was added sodium hydride (697 mg of a 60% dispersion in mineral oil, 17.4 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min, then tert-butyl bromoacetate (1.88 mL, 12.8 mmol) was added and stirring was continued at room temperature for 72 h. The reaction mixture was quenched with H₂O. The aqueous layer was extracted with CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 80:20, to provide the title compound. MS: m/z=399 (M+1).

Step C. 2-Oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetic acid

A solution of the tert-butyl 2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetate from Step B (3.19 g, 8.01 mmol) in CH₂Cl₂ (16 mL) and CF₃CO₂H (5 mL) was stirred at ambient temperature for 17 h. Added CF₃CO₂H (1 mL) and stirred 1 additional hour. The mixture was concentrated in vacuo. To the resulting solid was added an HCl solution (10 mL, 2.0 M in Et₂O) and the solution concentrated in vacuo. Repeated two more times to produce the hydrochloride salt of the title compound as a white solid. MS: m/z=343 (M+1).

Intermediate 12

[1′-(2,2,2-Trifluoroethyl)spiro[indole-3,4′-piperidin]-1 (21)-yl]acetic acid Step A. 1′-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]

A mixture of 1-acetyl-1,2-dihydrospiro[indole-3,4′-piperidine] hydrochloride, [Chen et al. Tetrahedron Lett. 1996, 37(30), 5233-5234] (200 mg, 0.750 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.128 mL, 0.900 mmol), and triethylamine (0.522 mL, 3.75 mmol) in acetone (2 mL) was heated at reflux for 15 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH₂Cl₂ (10 mL) and washed with saturated aqueous NaHCO₃ (10 mL). The aqueous layer was further extracted with CH₂Cl₂ (2×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to provide the title compound. MS: m/z=271 (M+1).

Step B. tert-Butyl[1′-(2,2,2-trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2H)-yl]acetate

A solution of 1′-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine] from Step A (64.0 mg, 0.237 mmol), potassium carbonate (49.0 mg, 0.355 mmol), potassium iodide (59.0 mg, 0.355 mmol), and tert-butyl bromoacetate (0.042 mL, 0.284 mmol) in DMF (2 mL) was stirred at 50° C. for 1 h. The reaction mixture was quenched with H₂O. The aqueous layer was extracted with CH₂Cl₂ (3×20 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=385 (M+1).

Step C. [1′-(2,2,2-Trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2-H)-yl]acetic acid

A solution of tert-butyl[1′-(2,2,2-trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2H)-yl]acetate (91.0 mg, 0.237 mmol) from Step B in CH₂Cl₂ (2 mL) and CF₃CO₂H (1 mL) was stirred at ambient temperature for 6 h. Added CF₃CO₂H (1 mL) and stirred 1 additional hour. The mixture was concentrated in vacuo. The crude product was partitioned between CH₂Cl₂ (20 mL) and saturated NaHCO₃ (20 mL). The layers were separated and the aqueous layer was further extracted with CH₂Cl₂ (2×20 mL). The combined CH₂Cl₂ layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=329 (M+1).

Intermediate 13

(±)-{3-[4-(Methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid Step A. 1-(4-Bromo-1,3-thiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one

A mixture of 2-hydroxybenzimidazole (1.20 g, 8.95 mmol), 2,4-dibromothiazole (6.50 g, 26.8 mmol), copper powder (1.42 g, 22.4 mmol), CuCl (177 mg, 1.79 mmol), and KOAc (2.20 g, 22.4 mmol) in pyridine (10 mL) were heated at 60° C. for 2 h. The cooled mixture was partitioned between EtOAc (40 mL) and 10% aqueous citric acid (20 mL) and the organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=298 (M+1).

Step B. 1-[4-(Methylthio)-1,3-thiazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-one

A mixture of 1-(4-bromo-1,3-thiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one from Step A (1.00 g, 3.38 mmol), sodium methanethiolate (710 mg, 10.13 mmol), and copper iodide (643 mg, 3.38 mmol) in DMF (6 mL) were heated at 140° C. An additional amount of sodium methanethiolate (474 mg, 6.76 mmol) was added to the mixture after 3 h and 16 h and the reaction continued stirring at 140° C. After 20 h, the cooled mixture was partitioned between saturated aqueous NaHCO₃ (30 mL) and CHCl₃ (50 mL). The aqueous phase was extracted further with CHCl₃ (50 mL) and the combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=264 (M+1).

Step C. tert-Butyl {3-[4-(methylthio)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate

To a stirred mixture of 1-[4-(methylthio)-1,3-thiazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-one from Step B (710 mg, 2.67 mmol) and tert-butyl bromoacetate (578 mg, 2.97 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (194 mg of a 60% dispersion in mineral oil, 4.85 mmol). The mixture was stirred at 0° C. for 15 min, then quenched with saturated aqueous NaHCO₃ and extracted with CH₂Cl₂ (2×35 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 70:30, to give the title compound. MS: m/z=378 (M+1).

Step D. (±)-tert-Butyl{3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate

A solution of OXONE® in H₂O (0.5 mL) was added to a solution of tert-butyl {3-[4-(methylthio)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step C (110 mg, 0.291 mmol) in isopropanol (1 mL) and CHCl₃ (1 mL) at 0° C. After 2 h, the mixture was quenched with saturated aqueous NaCl and extracted with CHCl₃ (2×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-90:10 to 50:50, to give the title compound. MS: m/z=394 (M+1).

Step E. (±)-{3-[4-(Methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid

(±)-tert-Butyl {3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step D (100 mg, 0.254 mmol) was dissolved in CF₃CO₂H (3 mL) and CH₂Cl₂ (3 mL) and the mixture was stirred at ambient temperature for 3 h, then concentrated in vacuo to give the title compound. MS: m/z=338 (M+1).

Intermediate 14

{3-[4-(Methoxycarbonyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid Step A. tert-Butyl[3-(4-bromo-1,3-thiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

Essentially following the procedures described for Intermediate 7, but using 2,4-dibromothiazole in place of 2-bromopyridine, the title compound was prepared. MS: m/z=412 (M+1).

Step B. Methyl 2-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1,3-thiazole-4-carboxylate

To a suspension of tert-butyl[3-(4-bromo-1,3-thiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (250 mg, 0.609 mmol) and triethylamine (0.850 mL, 6.09 mmol) in MeOH (5 mL) was added bis(triphenylphosphine)palladium (II) chloride (86.0 mg, 0.122 mmol). The reaction mixture was heated at reflux under an atmosphere of carbon monoxide (ca 1 atm) for 48 h, then partitioned between CHCl₃ (20 mL) and saturated aqueous NaHCO₃ (5 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 60:40, to give the title compound. MS: m/z=412 (M+23).

Step C. {3-[4-(Methoxycarbonyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid

A solution of methyl 2-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1,3-thiazole-4-carboxylate from Step B (195 mg, 0.501 mmol) in EtOAc (3 mL) at 0° C. was saturated with HCl (g) for 5 min. After 15 min, the reaction was re-saturated with HCl for another 5 min. The mixture was concentrated in vacuo to give the title compound as a white solid. MS: m/z=334 (M+1).

Intermediate 15

{3-[4-(Ethoxycarbonyl)phenyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid Step A. Ethyl 4-[(2-nitrophenyl)amino]benzoate

A mixture of ethyl 4-aminobenzoate (1.00 g, 6.05 mmol) and 2-fluoronitrobenzene (0.64 mL, 6.05 mmol) was heated at 160° C. for 18 h. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc-70:30, to give the title compound. MS: m/z=287 (M+1).

Step B. Ethyl 4-[(2-aminophenyl)amino]benzoate

A mixture of ethyl 4-[(2-nitrophenyl)amino]benzoate from Step A (755 mg, 2.64 mmol) and 10% Pd/C (505 mg) in EtOH (25 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 4 h. The mixture was filtered through a pad of Celite, washing with EtOH, and the filtrate was concentrated to give the title compound. MS: m/z=257 (M+1).

Step C. Ethyl 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate

A mixture of ethyl 4-[(2-aminophenyl)amino]benzoate from Step B (442 mg, 1.72 mmol) and 1,1′-carbonyldiimidazole (652 mg, 4.02 mmol) in THF (10 mL) was heated at 75° C. for 3 h. The cooled mixture was partitioned between EtOAc (100 mL) and 10% aqueous citric acid (50 mL). The organic layer was washed with H₂O (30 mL), then brine (30 mL), then dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 75:25, to give the title compound. MS: m/z=283 (M+1).

Step D. Ethyl 4-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]benzoate

To a stirred solution of ethyl 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate from Step C (590 mg, 2.09 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (104 mg of a 60% dispersion in mineral oil, 2.60 mmol). The mixture was stirred for 5 min, then tert-butyl bromoacetate (489 mg, 2.51 mmol) was added and stirring was continued for 3 h. The reaction mixture was partitioned between EtOAc (200 mL) and H₂O (100 mL). The organic layer was washed with H₂O (50 mL), then brine (50 mL), then dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=397 (M+1).

Step E. {3-[4-(Ethoxycarbonyl)phenyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetic acid

Essentially following the procedures described for Intermediate 7, but using ethyl 4-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]benzoate from Step D in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=341 (M+1).

Intermediate 16

(±)-(2-Oxo-3-tetrahydrofuran-3-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid Step A. (±)-N-(2-Nitrophenyl)tetrahydrofuran-3-amine

A solution of N,N-diisopropylethylamine (3.20 mL, 18.4 mmol), 1-fluoro-2-nitrobenzene (0.484 mL, 4.59 mmol), and (±)-tetrahydrofuran-3-amine (400 mg, 4.59 mmol) in n-butanol (10 mL) was heated to 180° C. in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, gave the title compound. MS: m/z=209 (M+1).

Step B. (±)-(2-Oxo-3-tetrahydrofuran-3-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid

Essentially following the procedures described for Intermediate 15, but using (±)-N-(2-nitrophenyl)tetrahydrofuran-3-amine in place of ethyl 4-[(2-nitrophenyl)amino]benzoate, the title compound was prepared. MS: m/z=263 (M+1).

Intermediate 17

(2-Oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid Step A. tert-Butyl 2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazole-1-carboxylate

Diethyl azodicarboxylate (446 mg, 2.56 mmol) was added to a solution of tert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (J. Org. Chem., 1995, 60, 1565-1582) (500 mg, 2.13 mmol), triphenylphosphine (672 mg, 2.56 mmol), and tetrahydro-2H-thiopyran-4-ol (Chem. Comm., 2002, 10, 1070-1071) (303 mg, 2.56 mmol) in THF (10 mL). After 20 h, the reaction was concentrated in vacuo and the crude product purified by silica gel column chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 95:5, to give the title compound. MS: m/z=335 (M+1).

Step B. 1-Tetrahydro-2H-thiopyran-4-yl-1,3-dihydro-2H-benzimidazol-2-one

CF₃CO₂H (1 mL) was added to a solution of tert-butyl 2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazole-1-carboxylate from Step A (210 mg, 0.628 mmol) in CH₂Cl₂ (3 mL). After 2 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=235 (M+1).

Step C. tert-Butyl (2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate

Sodium hydride (68.3 mg of a 60% dispersion in mineral oil, 1.71 mmol) followed by tert-butyl bromoacetate (0.189 mL, 1.28 mmol) was added to a solution of 1-tetrahydro-2H-thiopyran-4-yl-1,3-dihydro-2H-benzimidazol-2-one from Step B (200 mg, 0.854 mmol) in DMF (5 mL). After 1 h, the reaction was quenched with H₂O (10 mL) and extracted with CH₂Cl₂ (10 mL). The organic layer was washed with saturated NaHCO₃ (5 mL), dried over MgSO₄, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, gave the title compound. MS: m/z=349 (M+1).

Step D. (2-Oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid

CF₃CO₂H (1 mL) was added to a solution of tert-butyl (2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step C (169 mg, 0.485 mmol) in CH₂Cl₂ (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=293 (M+1).

Intermediate 18

(2-Oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetic acid Step A. 2′,3′,5′,6′-Tetrahydrospiro[indole-3,4′-pyran]-2(1H)-one

Butyllithium (2.5 M in hexanes, 3.76 mL, 9.39 mmol) was added to a solution of oxindole (500 mg, 3.76 mmol) at −78° C. in THF (40 mL). After complete addition, N,N,N′,N′-tetramethylethane-1,2-diamine (1.48 mL, 9.76 mmol) was added, maintaining the internal temperature <−70° C. After 1 h at −78° C., 2-iodoethyl ether (4.90 g, 15.0 mmol) was added and the reaction warmed to ambient temperature. After 48 h the reaction was quenched with H₂O (5 mL) and the mixture was partitioned between EtOAc (100 mL) and H₂O (100 mL). The aqueous solution was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 97:3, gave the title compound. MS: m/z=204 (M+1).

Step B. tert-Butyl (2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetate

Sodium hydride (8.00 mg of a 60% dispersion in mineral oil, 0.207 mmol) was added to a solution of 2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-2(1H)-one from Step A (35.0 mg, 0.172 mmol) in DMF (1 mL) at 0° C. After 1 hr, tert-butyl bromoacetate (0.280 mL, 0.189 mmol) was added and the reaction warmed to ambient temperature. After 18 h, the reaction was partitioned between CH₂Cl₂ (10 mL) and saturated NH₄Cl (10 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=318 (M+1).

Step C. (2-Oxo-2′,3′,5′,6-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetic acid

CF₃CO₂H (1 mL) was added to a solution of tert-butyl (2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetate from Step B (55.0 mg, 0.173 mmol) in CH₂Cl₂ (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).

Intermediate 19

(2′,4-Dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetic acid Step A. 4H-Spiro[cyclohexane-13′-indole]-2′,4(1′H)-dione

Methyl acrylate (10.5 mL, 116.4 mmol) was added over 1 h to a solution of oxindole (5.00 g, 37.6 mmol) and potassium tert-butoxide (211 mg, 1.88 mmol) in dimethyl sulfoxide (19 mL) at 45° C. After 1 h, potassium tert-butoxide (9.48 g, 84.5 mmol) was added in portions over 30 min while maintaining the internal temperature at 55-60° C. The mixture was concentrated in vacuo, poured into H₂O (100 mL), and heated to 80° C. After 23 h, the reaction was extracted with EtOAc (3×100 mL) and the combined organics were dried over Na₂SO₄, filtered, and concentrated to give the desired product. MS: m/z=216 (M+1).

Step B. tert-Butyl (2′,4-dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetate

Cesium carbonate (1.19 g, 3.64 mmol) was added to a solution of 4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione from Step A (523 mg, 2.43 mmol) and tert-butyl bromoacetate (0.431 mL, 2.92 mmol) in DMF (10 mL). After 22 h, the mixture was partitioned between H₂O (100 mL) and CH₂Cl₂ and extracted with CH₂Cl₂ (3×75 mL). The combined organics were washed with H₂O, dried over Na₂SO₄, filtered, and concentrated in vacuo to give the desired product. MS: m/z=330 (M+1).

Step C. (2′,4-Dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetic acid

HCl (g) was bubbled into a solution of tert-butyl (2′,4-dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetate from Step B (800 mg, 2.43 mmol) in EtOAc (10 mL) for 5 min. After 3 h, the reaction was concentrated in vacuo to give the desired product. MS: m/z=274 (M+1).

Intermediate 20

Sodium (5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate Step A. 3,3-Bis[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-indol-2-one

Potassium tert-butoxide (10.1 g, 90.1 mmol) was added to a solution of oxindole (3.00 g, 22.5 mmol) in THF (50 mL) at −75° C. and the mixture was allowed to warm to ambient temperature. After 1 h, the reaction was cooled to −75° C. and 2-(2-bromoethoxy)tetrahydro-2H-pyran (7.15 mL, 47.3 mmol) was added dropwise over 10 min. After 18 h, the mixture was partitioned between EtOAc (100 mL) and H₂O (100 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×50 mL). The combined organics were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 80:20, gave the title compound. MS: 71/z=390 (M+1).

Step B. 5-Bromo-3,3-bis(2-bromoethyl)-1,3-dihydro-2H-indol-2-one

Bromine (0.712 mL, 13.9 mmol) was added to a solution of 3,3-bis[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-indol-2-one from Step A (1.23 g, 3.16 mmol) and triphenylphosphine (3.64 g, 13.9 mmol) in CH₂Cl₂ (20 mL) at 0° C. After 22 h, the mixture was partitioned between CH₂Cl₂ (50 mL) and H₂O (50 mL). The layers were separated and the aqueous layer was further extracted with CH₂Cl₂ (2×25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 90:10, gave the title compound. MS: m/z=427 (M+1).

Step C. 5-Bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-2(1H)-one

Sodium sulfide (292 mg, 3.75 mmol) was added to a solution of 5-bromo-3,3-bis(2-bromoethyl)-1,3-dihydro-2H-indol-2-one from Step B (532 mg, 1.25 mmol) in DMF (2 mL) and the solution heated to 50° C. After 2.5 h, the mixture was partitioned between CH₂Cl₂ (20 mL) and H₂O (20 μL). The layers were separated and the aqueous layer was further extracted with CH₂Cl₂ (2×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=300 (M+1).

Step D. Ethyl (5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate

Cesium carbonate (610 mg, 1.87 mmol) was added to a solution of 5-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-2(1H)-one from Step C (372 mg, 1.25 mmol) and ethyl bromoacetate (0.166 mL, 1.50 mmol) in DMF (2 mL). After 16 h, H₂O (5 mL) was added to the reaction and the resulting precipitate was collected by filtration to give the title compound. MS: m/z=386 (M+1).

Step E. Sodium (5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate

5 M Sodium hydroxide solution (0.748 mL, 3.74 mmol) was added to a solution of ethyl (5-bromo-2-oxo-2′,3′,51,61-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate from Step D (479 mg, 1.25 mmol) in EtOH(2 mL) and the mixture was heated to 60° C. After 14 h, H₂O (5 mL) was added to the reaction and the resulting precipitate was collected by filtration to give the desired product. MS: m/z=357 (M+1).

Intermediate 21

(2-Oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetic acid Step A. (2-Oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetic acid

Ethylmagnesium bromide (3 M in Et₂O, 0.272 mL, 0.817 mmol) was added to a solution of sodium (5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate (194 mg, 0.545 mmol, described in Intermediate 20) in THF (5 mL) at −78° C., followed by the addition of tert-butyllithium (1.7 M in pentane, 0.801 mL, 1.36 mmol). After 1 h, the reaction was quenched with H₂O and partitioned between EtOAc (20 mL) and 10% HCl (20 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=278 (M+1).

Intermediate 22

[3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-1H-indol-1-yl]acetic acid Step A. [(4,6-Dimethyl-1H-indol-3-yl)methyl]dimethylamine

A mixture of 4,6-dimethyl-1H-indole (Cho et al., Tetrahedron, 2001, 57, 3321-3330) (93.0 mg, 0.640 mmol) and N,N,N′tetramethylmethanediamine (98.0 mg, 0.961 mmol) in AcOH (3 mL) was stirred at ambient temperature for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO₃ (10 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound.

Step B. (4,6-Dimethyl-1H-indol-3-yl)acetonitrile

A solution of [(4,6-dimethyl-1H-indol-3-yl)methyl]dimethylamine from Step A (98.0 mg, 0.484 mmol) and potassium cyanide (315 mg, 4.84 mmol) in DMF (2 mL) and H₂O (2 mL) was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaCl (10 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 98:2, gave the title compound. MS: m/z=185 (M+1).

Step C. Methyl (4,6-dimethyl-1H-indol-3-yl)acetate

HCl (g) was bubbled through a solution of (4,6-dimethyl-1H-indol-3-yl)acetonitrile from Step B (83.0 mg, 0.450 mmol) in MeOH (5 mL). The reaction mixture was stirred for 30 min, then H₂O (1 mL) was added and stirring was continued for 2 h. The MeOH was removed under vacuum and the reaction mixture was extracted with EtOAc (5 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was dissolved in MeOH (2 mL) containing a drop of conc. H₂SO₄ and the resulting mixture was stirred for 16 h. The reaction mixture was partitioned between EtOAc (10 mL) and saturated NaCl (5 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 80:20, gave the title compound. MS: m/z=218 (M+1).

Step D. [3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-1H-indol-1-yl]acetic acid

Essentially following the procedures described for Intermediate 19, but using methyl (4,6-dimethyl-1H-indol-3-yl)acetate from Step C in place of 4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione the title compound was prepared. MS: m/z=276 (M+1).

Intermediate 23

[3-(2-Methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]acetic acid Step A. [(4-Bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]dimethylamine

A mixture of 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine (Zhang et al., J. Org. Chem., 2002, 67, 2345-2347) (200 mg, 0.864 mmol), formaldehyde (37 wt. % in H₂O, 0.500 mL, 6.17 mmol), and dimethylamine (40 wt. % in H₂O, 1.00 mL, 8.88 mmol) in AcOH (6 mL) was heated in a microwave reactor at 100° C. for 40 min. The solvent was removed under reduced pressure. The crude product was partitioned between CH₂Cl₂ (15 mL) and saturated NaHCO₃ (10 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 90:10, gave the title compound. MS: m/z=290 (M+1).

Step B. (4-Bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetonitrile

A solution of [(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]dimethylamine from Step A (195 mg, 0.676 mmol) and potassium cyanide (440 mg, 6.76 mmol) in DMF (0.5 mL) and H₂O (0.5 mL) was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and H₂O (10 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=272 (M+1).

Step C. Methyl (4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetate

HCl (g) was bubbled through a solution of (4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetonitrile from Step B (165 mg, 0.610 mmol) in MeOH (5 mL) and the reaction mixture was stirred for 2 h. The MeOH was removed under reduced pressure and H₂O (1 mL) and saturated NaHCO₃ (5 mL) were added. The reaction mixture was extracted with EtOAc (10 mL). The organic layer was washed with saturated NaHCO₃ (5 mL) and saturated NaCl (5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 90:10, gave the title compound. MS: m/z=305 (M+1).

Step D. tert-Butyl methyl 2,2′-(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine-1,3-diyl)diacetate

Cesium carbonate (185 mg, 0.568 mmol) was added to a solution of methyl (4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetate from Step C (115 mg, 0.379 mmol) and tert-butyl bromoacetate (0.0810 mL, 0.417 mmol) in DMF (2 mL). After 30 min, the mixture was partitioned between H₂O (5 mL) and EtOAc (10 mL). The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound. MS: m/z=419 (M+1).

Step E. [4-Bromo-7-chloro-3-(2-methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]acetic acid

1 M Sodium hydroxide solution (0.300 mL, 3.00 mmol) was added to a solution of tert-butyl methyl 2,2′-(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine-1,3-diyl)diacetate from Step D (153 mg, 0.366 mmol) in MeOH (3 mL) and the mixture was stirred for 2 h at ambient temperature. The reaction was quenched by the addition of 1 M HCl (0.300 mL) and the solvent removed under reduced pressure. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1 to provide the title compound. MS: m/z=363 (M+1).

Step F. [3-(2-Methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]acetic acid

A mixture of [4-bromo-7-chloro-3-(2-methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]acetic acid from Step E (27.0 mg, 0.075 mmol) and 10% Pd/C (10 mg) in MeOH (5 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 2 h. The mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=249 (M+1).

Intermediates 24-36

Essentially following analogous procedures to those outlined for Intermediates 7-23, the compounds listed in Table 1 were prepared. The most relevant analogous procedure for each intermediate is listed in the Table. The requisite starting materials were commercially available, described in the literature, or readily synthesized by one skilled in the art of organic synthesis. In some cases, straightforward protecting group strategies were applied. TABLE 1

MS Relevant Literature Intermediate R^(c) (M + 1) Intermediate Reference 24

285 7 25

271 7 26

271 7 27

271 8 28

322 13 29

354 13 30

362 16 31

328 7 32

361 11 33

276 7 34

324 22 Snieckus et al., Org. Lett., 2002, 4(5), 815-818. 35

325 22 Snieckus et al., Org Lett., 2002, 4(5), 815-818. 36

271 8 37

264 10 38

304 22

EXAMPLE 1

(±)-N-(2′,5′-Dioxo-1,3-dihydrospiro[indene-2,3′-pyrrolidin]-5-yl)-2-(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetamide

A solution of (±)-5-amino-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione (50.0 mg, 0.231 mmol, described in Intermediate 3), 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (62.0 mg, 0.231 mmol, described in Intermediate 7), EDC (53.0 mg, 0.277 mmol), HOBT (42.0 mg, 0.277 mmol), and triethylamine (0.0890 mL, 0.509 mmol) were stirred for 16 h at ambient temperature in DMF (2 mL). The reaction mixture was partitioned between saturated NaHCO₃ (3 mL) and EtOAc (5 mL). The layers were separated and the organic layer was washed with H₂O (3 mL) and 10% citric acid (3 mL), then dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 90:10, gave the title compound. MS: 7/z=468 (M+1). HRMS: m/z=468.1671; calculated m/z=468.1667 for C₂₆H₂₂N₅O₄.

EXAMPLE 2

(±)-N-(4′-Chloro-6′-oxo-1,3,6′,7′-tetrahydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-5-yl)-2-(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetamide

Essentially following the procedure described for Example 1, but using Intermediate 6 in place of Intermediate 3, the title compound was obtained. MS: m/z=538 (M+1). HRMS: m/z=538.1376; calculated m/z=538.1389 for C₂₈H₂₁ClN₇O₃.

EXAMPLE 3

(±)-2-(2-Oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)-N-(6′-oxo-1,3,6′,7′-tetrahydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-5-yl)acetamide

Essentially following the procedure described for Example 1, but using Intermediate 5 in place of Intermediate 3, the title compound was obtained. MS: m/z=504 (M+1). HRMS: m/z=504.1769; calculated 771/Z=504.1778 for C₂₈H₂₂N₇O₃.

EXAMPLE 4

(±)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)-2-[2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide

Essentially following the procedure described for Example 1, but using Intermediate 2 in place of Intermediate 3, and Intermediate 33 in place of Intermediate 7, the title compound was obtained. MS: m/z=508 (M+1). HRMS: m/z=508.1425; calculated m/z=508.1438 for C₂₈H₂₁N₅O₃S.

EXAMPLES 5-10

Essentially following the procedure outlined for Example 1, but using Intermediate 1 in place of Intermediate 3, the compounds listed in Table 2 were prepared. The requisite carboxylic acids were commercially available, described in the literature, synthesized according to methodology described herein (vide supra), or readily synthesized by one skilled in the art of organic synthesis. In some cases, straightforward protecting group strategies were applied. TABLE 2

MS Example R^(b) (M + 1) 5

454 6

477 7

462 8

545 9

445 10

527

EXAMPLES 11-41

Essentially following the procedure outlined for Example 1, but using Intermediate 4 in place of Intermediate 3, the compounds listed in Table 3 were prepared. The requisite carboxylic acids were commercially available, described in the literature, synthesized according to methodology described herein (vide supra), or readily synthesized by one skilled in the art of organic synthesis. In some cases, straightforward protecting group strategies were applied. TABLE 3

Example R^(b) MS (M + 1) 11

503 12

504 13

504 14

518 15

504 16

555 17

587 18

576 19

562 20

526 21

540 22

539 23

539 24

571 25

496 26

563 27

504 28

567 29

495 30

507 31

509 32

591 33

495 34

561 35

526 36

511 37

509 38

557 39

570 40

558 41

482 42

522 43

508 44

497

EXAMPLE 45

cis-2-[3-(1-Oxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)acetamide, enantiomer B

Sodium periodate (9 mg, 0.043 mmol) was added to a solution of N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide, enantiomer B (19 mg, 0.036 mmol, described in Example 35) in H₂O (1 mL). After 20 h, the reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1 to provide the title compound. MS: n7/z=542 (M+1). HRMS: m/z=542.1846; calculated m/z=542.1857 for C₂₉H₂₈N₅O₄S.

EXAMPLE 46

trans-2-[3-(1-Oxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)acetamide, enantiomer B

Following the procedure outlined for Example 45, the title compound was obtained as a white solid. MS: m/z=542 (M+1). HRMS: m/z=542.1847; calculated m/z=542.1857 for C₂₉H₂₈N₅O₄S.

EXAMPLE 47

cis-2-(1′-Oxido-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide, enantiomer B

Following the procedures outlined for Example 45, but using N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-(2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetamide, enantiomer B (described in Example 36) in place of (±)-N-(2′-oxo-1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide, enantiomer B (described in Example 35), the title compound was obtained as a white solid. MS: m/z=527 (M+1). HRMS: m/z=527.1726; calculated m/z=527.1748 for C₂₉H₂₇N₄O₄S.

EXAMPLE 48

trans-2-(1′-Oxido-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide, enantiomer B

Following the procedure outlined for Example 47, the title compound was obtained as a white solid. MS: m/z=527 (M+1). HRMS: m/z=527.1727; calculated m/z=527.1748 for C₂₉H₂₇N₄O₄S.

EXAMPLE 49

2-[3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide, enantiomer B

OXONE® (35.0 mg, 0.057 mmol) in H₂O (1 mL) was added to a solution of N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide, enantiomer B (10.0 mg, 0.019 mmol, described in Example 35) in isopropanol (1 mL) and CHCl₃ (1 mL). After 20 h, the reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1 to provide the title compound. MS: m/z=558 (M+1). HRMS: m/z=558.1783; calculated m/z=558.1806 for C₂₉H₂₇N₅O₅S

EXAMPLE 50

2-(5-Bromo-1′1′-dioxido-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1 (2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide enantiomer B

Following the procedures outlined for Example 49, but using 2-(5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1 (2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-h]pyridin]-5-yl)acetamide, enantiomer B (described in Example 32) in place of N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide, enantiomer B (described in Example 35), the title compound was obtained as a white solid. MS: m/z=621 (M+1). HRMS: m/z=621.0794; calculated m/z=621.0802 for C₂₉H₂₆BrN₄O₅S

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable. 

1. A compound of formula I:

wherein: B is a bicycloheterocycle selected from the group consisting of:

where T, U, V, W, X and Y are each independently a carbon atom or a nitrogen atom, wherein no more than two of T, U, V and W, and no more than three of T, U, V, W, X and Y, are a nitrogen atoms, B is unsubstituted or substituted with 1-5 substituents each independently selected from R¹, R², R^(3a) and R^(3b), wherein R¹, R², R^(3a) and R^(3b) are independently selected from: (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₁₆alkyl, (d) —C₃₋₆cycloalkyl, (e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy, trifluoromethyl and —OCF₃, (f) —CO₂R⁹, wherein R⁹ is independently selected from: hydrogen, —C₁₋₆alkyl which is unsubstituted or substituted with 1-6 fluoro, —C₃₋₆cycloalkyl, benzyl and phenyl, (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently selected from: hydrogen, —C₁₋₆alkyl which is unsubstituted or substituted with 1-6 fluoro, —C₅₋₆cycloalkyl, benzyl, phenyl, —COR⁹ and —SO₂R¹², (h) —SO₂R¹², wherein R¹² is independently selected from: —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 fluoro, —C₅₋₆cycloalkyl, benzyl and phenyl, (i)—CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each independently selected from: hydrogen, —C₁₋₆alkyl which is unsubstituted or substituted with 1-6 fluoro, —C₅₋₆cycloalkyl, benzyl and phenyl,  or R^(10a) and R^(11a) are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxyl, phenyl and benzyl, (j) trifluoromethyl, (k) —OCO₂R⁹, (l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), (n) —(NR⁹)(CO)NR^(10a)R^(11a), and (o) —O—C₃₋₆cycloalkyl, (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₆alkyl, (d) trifluoromethyl, (e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy and trifluoromethyl, (3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl, benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl, benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl, pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl, purinyl, naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 fluoro, (b) halo, (c) hydroxy, (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 fluoro, (e) —C₃₋₆cycloalkyl, (f) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl,  which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy and trifluoromethyl, (g) —CO₂R⁹, (h) —(CO)R⁹, (i) —NR¹⁰R¹¹, (j) —CONR¹⁰R¹¹, (k) oxo (l) —SR¹², (m) —S(O)R¹², and (n) —SO₂R¹², (4) halo, (5) oxo, (6) hydroxy, (7) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5 halo, (8) —CN, (9) —CO₂R⁹, (10) —NR¹⁰R¹¹, (11) —SO₂R¹², (12) —CONR^(10a)R^(11a), (13) —OCO₂R⁹, (14) —(NR^(10a))CO₂R⁹, (15) —O(CO)NR^(10a)R^(11a), (16) —(NR⁹)(CO)NR^(10a)R^(11a), (17) —(CO)—(CO)NR^(10a)R^(11a), (18) —(CO)—(CO)OR⁹, and (19) —SO₂NR^(10a)R^(11a); or R^(3a) and R^(3b) and the carbon atom(s) to which they are attached are joined to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, dihydrothiopyranyl, tetrahydrothiopyranyl and piperazinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from: (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: (i) halo, (ii) hydroxy, (iii) —O—C₁₋₆alkyl, (iv) —C₃₋₆cycloalkyl, (v) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy, trifluoromethyl and —OCF₃, (vi) —CO₂R⁹, (vii) —NR¹⁰R¹¹, (viii) —SO₂R¹², (ix) —CONR^(10a)R^(11a), and (x)—(NR^(10a))CO₂R⁹, (b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C₁₋₆alkyl which is unsubstituted or substituted with 1-6 fluoro, halo, hydroxy, —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 fluoro, and —C₃₋₆cycloalkyl, (c) halo, (d) —SO₂R¹², (e) hydroxy, (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (g) —CN, (h) —COR¹², (i) —NR¹⁰R¹¹, (j) —CONR^(10a)R^(11a), (k) —CO₂R⁹, (l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), (n) —(NR⁹)(CO)NR^(10a)R^(11a), and (o) oxo; A¹ and A² are each independently selected from: a bond and —CR¹³R¹⁴—, wherein R¹³ and R¹⁴ are each independently selected from: hydrogen, C₁₋₆ alkyl which is unsubstituted or substituted with 1-6 fluoro, hydroxy and halo, wherein one of A¹ and A² is optionally absent; J is independently selected from: ═C(R^(6a))—, —CR¹³R¹⁴— and —C(═O)—; K is independently selected from: ═C(R^(6b))—, —CR¹³R¹⁴—, —C(═O)—, —SO₂—, ═N— and —N(R^(6b))—; R⁴ is independently selected from: hydrogen, C₁₋₆ alkyl which is unsubstituted or substituted with 1-6 fluoro, C₅₋₆ cycloalkyl, benzyl and phenyl; R^(5a), R^(5b) and R^(5c) are each independently selected from: hydrogen, C₁₋₆ alkyl, —O—C₁₋₆alkyl, —OCF₃, trifluoromethyl, halo, hydroxy and —CN; R^(6a) and R^(6b) are each independently selected from: (1) hydrogen; (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: (a) halo, (b) —O—C₁₋₆alkyl, (c) —C₃₋₆cycloalkyl, (d) phenyl or heterocycle, wherein heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 each independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy, trifluoromethyl and —OCF₃, (3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C₁₋₄-alkyl which is unsubstituted or substituted with 1-5 fluoro, —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-5 fluoro, halo, hydroxy, —C₃₋₆cycloalkyl and phenyl, (4) halo, (5) hydroxy, (6) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5 halo, (7) —CN, (8) —CO₂R⁹, (9) —NR¹⁰R¹¹, and (10) —CONR^(10a)R^(11a); or R^(6a) and R^(6b) and the atom(s) to which they are attached are joined to form a ring selected from cyclopentenyl, cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, dihydrofuranyl, dihydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thienyl, dihydrothienyl and dihydrothiopyranyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from: (a) —C₁₋₆alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from: (i) halo, (ii) hydroxy, (iii) —O—C₁₋₆alkyl, (iv) —C₃₋₆cycloalkyl, (v) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy, trifluoromethyl and —OCF₃, (vi) —CO₂R⁹, (vii) —NR¹⁰R¹¹, (viii) —SO₂R¹², (ix) —CONR^(10a)R^(11a) and (x) —(NR^(10a))CO₂R⁹, (b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C₁₋₆alkyl which is unsubstituted or substituted with 1-6 fluoro, —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-6 fluoro, halo, hydroxyl and —C₃₋₆cycloalkyl, (c) halo, (d) —SO₂R¹², (e) hydroxy, (f) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5 halo, (g) —CN, (h) —COR¹², (i) —NR¹⁰R¹¹, (j) —CONR^(10a)R^(11a), (k) —CO₂R⁹, (l) —(NR^(10a))CO₂R⁹, (m) —O(CO)NR^(10a)R^(11a), (n) —(NR⁹)(CO)NR^(10a)R^(11a), and (o) oxo; m is 1 or 2; n is 1 or 2; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 2. The compound of claim 1, of the formula Ia:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 3. The compound of claim 1, of the formula Ib:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 4. The compound of claim 1, of the formula Ic:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 5. The compound of claim 1, of the formula Id:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 6. The compound of claim 1, of the formula Ie:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 7. The compound of claim 1, of the formula If:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 8. The compound of claim 1, of the formula Ig:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
 9. The compound of claim 1, wherein B is selected from:

where B is unsubstituted or substituted with 1-5 substituents selected from R¹, R², R^(3a).
 10. The compound of claim 1, wherein B is selected from: 2-oxobenzimidazolinyl, is indolyl, indolinyl, 2-oxoindolinyl, 2-oxoazabenzimidazolinyl and azaindolyl.
 11. The compound of claim 1, wherein R¹, R², R^(3a) and R^(3b) are independently selected from: (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: (a) fluoro, (b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, (c) —CO₂R⁹, wherein R⁹ is independently selected from: hydrogen, and —C₁₋₆alkyl, (d) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each independently selected from: hydrogen and —C₁₋₆alkyl,  or R^(10a) and R^(11a) are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, and (e) —O—C₃₋₆cycloalkyl, (2) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, thiazolyl, isothiazolyl, 2-oxopyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydrothienyl and tetrahydrothiopyranyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 fluoro, (b) halo, (c) —CO₂R⁹, wherein R⁹ is selected from: hydrogen, —C₁₋₄alkyl, and —C₃₋₆cycloalkyl, (d) —(CO)R⁹, (e) CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are independently selected from: hydrogen and —C₁₋₆alkyl,  or R^(10a) and R^(11a) are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 fluoro, (g) hydroxy, (h) oxo, (i) —S—C₁₋₄alkyl, (j) —S(O)—C₁₋₄alkyl, and (k) —SO₂—C₁₋₄alkyl, (3) halo, (4) hydroxy, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 fluoro, (6) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently selected from: hydrogen, —C₁₋₄alkyl which is unsubstituted or substituted with 1-5 fluoro, —C₅₋₆cycloalkyl, and —COR⁹; (7) —C₃₋₆cycloalkyl, (8) —(CO)—(CO)NR^(10a)R^(11a), wherein R^(10a) and R^(11a) are independently selected from: hydrogen and —C₁₋₆alkyl, and (9) —CN.
 12. The compound of claim 1, A¹ is a bond.
 13. The compound of claim 1, wherein A² is —CH₂—.
 14. The compound of claim 1, wherein J is selected from: ═C(R^(6a))— and —CH₂—.
 15. The compound of claim 1, wherein K is selected from: ═C(R^(6b))—, —CH₂—, and —C(═O)—.
 16. The compound of claim 1, wherein R⁴ is selected from: hydrogen and —C₁₋₆alkyl which is unsubstituted or substituted with fluoro.
 17. The compound of claim 1, wherein R^(5a), R^(5b) and R⁵— are independently selected from hydrogen, C₁₋₆alkyl and halo.
 18. The compound of claim 1, wherein R^(6a) and R^(6b) are independently selected from: (1) hydrogen; (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, —O—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and phenyl, (3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from: —C₁₋₄alkyl which is unsubstituted or substituted with 1-3 fluoro, —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 fluoro, halo and hydroxyl, (4) halo, (5) —NR¹⁰R¹¹, (6) hydroxy, and (7) —O—C₁₋₄alkyl which is unsubstituted or substituted with 1-3 halo.
 19. The compound of claim 1, wherein R^(6a) and R^(6b) and the atom(s) to which they are attached are joined to form a ring selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl and thienyl, which ring is unsubstituted or substituted with 1-3 substituents each independently selected from: (a) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, —O—C₁₋₆alkyl, —CO₂R⁹, —NR¹⁰R¹¹ and —CONR^(10a)R^(11a), (b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5 fluoro, —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 fluoro, halo and hydroxyl, (c) halo, (d) hydroxy, (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (f) —CN, (g) —NR¹⁰R¹¹, (h) —CONR^(10a)R^(11a), and (i) oxo.
 20. A compound selected from:

and pharmaceutically acceptable salts and individual diastereomers thereof.
 21. A pharmaceutical composition which comprises an inert carrier and the compound of claim
 1. 22. A method for antagonism of CGRP receptor activity in a mammal which comprises the administration of an effective amount of the compound of claim
 1. 23. A method for treating, controlling, ameliorating or reducing the risk of headache, migraine or cluster headache in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of the compound of claim
 1. 24. A method of treating or preventing migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from serotonin agonists, analgesics, anti-inflamatory agents, anti-hypertensives and anticonvulsants.
 25. The method of claim 24, wherein said second agent is selected from a 5HT_(1B/1D) agonist, a 5HT_(1D) agonist, and a 5HT_(1F) agonist.
 26. The method of claim 25, wherein said second agent is selected from rizatriptan, sumatriptan, naratriptan, zolmitriptan, almotriptan, eletriptan, avitriptan, frovatriptan, LY334370 and PNU-142633.
 27. The method of claim 24, wherein said second agent is selected from ergotamine and dihydroergotamine.
 28. The method of claim 24, wherein said second agent is aspirin or acetaminophen.
 29. The method of claim 24, wherein said second agent is a glucocorticoid.
 30. The method of claim 24, wherein said second agent is a non-steroidal anti-inflammatory agent.
 31. The method of claim 30, wherein said second agent is selected from ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, olsalazine and sulfasalazine.
 32. The method of claim 24, wherein said second agent is an anticonvulsant selected from topiramate, zonisamide, divalproex sodium, pregabalin, gabapentin, levetiracetam, lamotrigine and tiagabine.
 33. The method of claim 24, wherein said second agent is selected from angiotensin II antagonists, angiotensin I antagonists, angiotensin converting enzyme inhibitors, and renin inhibitors.
 34. The method of claim 33, wherein said second agent is selected from losartan, candesartan, candesartan cilexetil, irbesartan, valsartan, eprosartan, telmisartan, olmesartan, medoxomil, captopril, benazepril, quinapril, perindopril, ramipril, trandolapril, lisinopril, and enalapril.
 35. A method of treating or preventing migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from anti-anxiety agents and neuroleptics.
 36. The method of claim 35, wherein said second agent is selected from, diazepam, alprazolam, chlordiazepoxide, olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine.
 37. A method of treating or preventing migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from beta-blockers and calcium channel blockers.
 38. The method of claim 37, wherein said second agent is selected from timolol, propanolol, atenolol, metoprolol, nadolol, flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, prochlorperazine and civamide.
 39. A method of treating or preventing migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from anti-depressants, selective serotonin reuptake inhibitors, and NE reuptake inhibitors.
 40. The method of claim 39, wherein said second agent is selected from amitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine, doxepin, protriptyline, desipramine, trimipramine, fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, and citalopram.
 41. A method of treating or preventing migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from botulinum toxins A or B.
 42. A method of treating or preventing migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from vanilloid receptor antagonists, adenosine 1 antagonists, NR2B antagonists, substance P antagonists, granzyme B inhibitors, endothelin antagonists, norepinephrin precursors, nitric oxide synthase inhibitors, neuroleptics, bradykinin antagonists, gap junction inhibitors, AMPA/KA antagonists, sigma receptor agonists, chloride channel enhancers, monoamine oxidase inhibitors, opioid agonists, and leukotriene receptor antagonists.
 43. The method of claim 42, wherein said second agent is selected from montelukast and zafirlukast.
 44. The method of claim 42, wherein said second agent is aprepitant.
 45. A method of treating or preventing migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from the group consisting of anti-emetics, prokinetics, and histamine H₁ antagonists.
 46. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from serotonin agonists, analgesics, anti-inflamatory agents, and anticonvulsants.
 47. The composition of claim 46, wherein said second agent is selected from a 5HT_(1B/1D) agonist, a 5HT_(1D) agonist, and a 5HT_(1F) agonist.
 48. The composition of claim 47, wherein said second agent is selected from rizatriptan, sumatriptan, naratriptan, zolmitriptan, almotriptan, eletriptan, avitriptan, frovatriptan, LY334370 and PNU-142633.
 49. The composition of claim 46, wherein said second agent is selected from ergotamine and dihydroergotamine.
 50. The composition of claim 46, wherein said second agent is aspirin or acetaminophen.
 51. The composition of claim 46, wherein said second agent is a glucocorticoid.
 52. The composition of claim 46, wherein said second agent is a non-steroidal anti-inflammatory agent.
 53. The composition of claim 52, wherein said second agent is selected from ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, olsalazine and sulfasalazine.
 54. The composition of claim 46, wherein said second agent is an anticonvulsant selected from topiramate, zonisamide, divalproex sodium, pregabalin, gabapentin, levetiracetam, lamotrigine and tiagabine.
 55. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from angiotensin II antagonists, angiotensin I antagonists, angiotensin converting enzyme inhibitors, and renin inhibitors.
 56. The composition of claim 55, wherein said second agent is selected from losartan, candesartan, candesartan cilexetil, irbesartan, valsartan, eprosartan, telmisartan, olmesartan, medoxomil, captopril, benazepril, quinapril, perindopril, ramipril, trandolapril, lisinopril, and enalapril.
 57. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from anti-anxiety agents and neuroleptics.
 58. The composition of claim 57, wherein said second agent is selected from, diazepam, alprazolam, chlordiazepoxide, olanzapine, droperidol, prochlorperazine, chlorpromazile and quetiapine.
 59. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from beta-blockers and calcium channel blockers.
 60. The composition of claim 59, wherein said second agent is selected from timolol, propanolol, atenolol, metoprolol, nadolol, flunarizine, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, verapamil, nifedipine, prochlorperazine and civamide.
 61. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from anti-depressants, selective serotonin reuptake inhibitors, and NE reuptake inhibitors.
 62. The composition of claim 61, wherein said second agent is selected from amitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine, doxepin, protriptyline, desipramine, trimipramine, fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, and citalopram.
 63. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from botulinuin toxins A or B.
 64. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second agent selected from vanilloid receptor antagonists, adenosine 1 antagonists, NR2B antagonists, substance P antagonists, granzyme B inhibitors, endothelin antagonists, norepinephrin precursors, nitric oxide synthase inhibitors, neuroleptics, bradykinin antagonists, gap junction inhibitors, AMPA/KA antagonists, sigma receptor agonists, chloride channel enhancers, monoamine oxidase inhibitors, opioid agonists, and leukotriene receptor antagonists.
 65. The composition of claim 64, wherein said second agent is selected from montelukast and zafirlukast.
 66. The composition of claim 64, wherein said second agent is aprepitant.
 67. A pharmaceutical composition comprising: a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second agent selected from the group consisting of anti-emetics, prokinetics, and histamine H1 antagonists. 